This invention is directed generally to proteinase (also known as xe2x80x9cproteasexe2x80x9d) inhibitors, and, more particularly, to aromatic sulfone hydroxamates (also known as xe2x80x9caromatic sulfone hydroxamic acidsxe2x80x9d) that, inter alia, inhibit matrix metalloproteinase (also known as xe2x80x9cmatrix metalloproteasexe2x80x9d or xe2x80x9cMMPxe2x80x9d) activity and/or aggrecanase activity. This invention also is directed to compositions of such inhibitors, intermediates for the syntheses of such inhibitors, methods for making such inhibitors, and methods for preventing or treating conditions associated with MMP activity and/or aggrecanase activity, particularly pathological conditions.
Connective tissue is a required component of all mammals. It provides rigidity, differentiation, attachments, and, in some cases, elasticity. Connective tissue components include, for example, collagen, elastin, proteoglycans, fibronectin, and laminin. These biochemicals make up (or are components of) structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea, and vitreous humor.
Under normal conditions, connective tissue turnover and/or repair processes are in equilibrium with connective tissue production. Degradation of connective tissue is carried out by the action of proteinases released from resident tissue cells and/or invading inflammatory or tumor cells.
Matrix metalloproteinases, a family of zinc-dependent proteinases, make up a major class of enzymes involved in degrading connective tissue. Matrix metalloproteinases are divided into classes, with some members having several different names in common use. Examples are: MMP-1 (also known as collagenase 1, fibroblast collagenase, or EC 3.4.24.3); MMP-2 (also known as gelatinase A, 72 kDa gelatinase, basement membrane collagenase, or EC 3.4.24.24), MMP-3 (also known as stromelysin 1 or EC 3.4.24.17), proteoglycanase, MMP-7 (also known as matrilysin), MMP-8 (also known as collagenase II, neutrophil collagenase, or EC 3.4.24.34), MMP-9 (also known as gelatinase B, 92 kDa gelatinase, or EC 3.4.24.35), MMP-10 (also known as stromelysin 2 or EC 3.4.24.22), MMP-1 I (also known as stromelysin 3), MMP-12 (also known as metalloelastase, human macrophage elastase or HME), MMP-13 (also known as collagenase 111), and MMP-14 (also known as MT1-MMP or membrane MMP). See, generally, Woessner, J. F., xe2x80x9cThe Matrix Metalloprotease Familyxe2x80x9d in Matrix Metalloproteinases, pp.1-14 (Edited by Parks, W. C. and Mecharn, R. P., Academic Press, San Diego, Calif. 1998).
Excessive breakdown of connective tissue by MMPs is a feature of many pathological conditions. Inhibition of MMPs therefore provides a control mechanism for tissue decomposition to prevent and/or treat these pathological conditions. Such pathological conditions generally include, for example, tissue destruction, fibrotic diseases, pathological matrix weakening, defective injury repair, cardiovascular diseases, pulmonary diseases, kidney diseases, liver diseases, ophthalmologic diseases, and diseases of the central nervous system. Specific examples of such conditions include, for example, rheumatoid arthritis, osteoarthritis, septic arthritis, multiple sclerosis, a decubitis ulcer, corneal ulceration, epidermal ulceration, gastric ulceration, tumor metastasis, tumor invasion, tumor angiogenesis, periodontal disease, liver cirrhosis, fibrotic lung disease, emphysema, otosclerosis, atherosclerosis, proteinuria, coronary thrombosis, dilated cardiomyopathy, congestive heart failure, aortic aneurysm, epidermolysis bullosa, bone disease, Alzheimer""s disease, defective injury repair (e.g., weak repairs, adhesions such as post-surgical adhesions, and scarring), post-myocardial infarction, bone disease, and chronic obstructive pulmonary disease.
Matrix metalloproteinases also are involved in the biosynthesis of tumor necrosis factors (TNFs). Tumor necrosis factors are implicated in many pathological conditions. TNF-xcex1, for example, is a cytokine that is presently thought to be produced initially as a 28 kD cell-associated molecule. It is released as an active, 17 kD form that can mediate a large number of deleterious effects in vitro and in vivo. TNF-xcex1 can cause and/or contribute to the effects of inflammation (e.g., rheumatoid arthritis), autoimmune disease, graft rejection, multiple sclerosis, fibrotic diseases, cancer, infectious diseases (e.g., malaria, mycobacterial infection, meningitis, etc.), fever, psoriasis, cardiovascular diseases (e.g., post-ischemic reperfusion injury and congestive heart failure), pulmonary diseases, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage, and acute phase responses like those seen with infections and sepsis and during shock (e.g., septic shock and hemodynamic shock). Chronic release of active TNF-xcex1 can cause cachexia and anorexia. TNF-xcex1 also can be lethal.
Inhibiting TNF (and related compounds) production and action is an important clinical disease treatment. Matrix metalloproteinase inhibition is one mechanism that can be used. MMP (e.g., collagenase, stromelysin, and gelatinase) inhibitors, for example, have been reported to inhibit TNF-xcex1 release. See, e.g., Gearing et al. Nature 376, 555-557 (1994). See also, McGeehan et al. See also, Nature 376, 558-561 (1994). MMP inhibitors also have been reported to inhibit TNF-xcex1 convertase, a metalloproteinase involved in forming active TNF-xcex1. See, e.g., WIPO Int""l Pub. No. WO 94/24140. See also, WIPO Int""l Pub. No. WO 94/02466. See also, WIPO Int""l Pub. No. WO 97/20824.
Matrix metalloproteinases also are involved in other biochemical processes in mammals. These include control of ovulation, post-partum uterine involution, possibly implantation, cleavage of APP (xcex2-amyloid precursor protein) to the amyloid plaque, and inactivation of (xcex11-protease inhibitor (xcex11-PI). Inhibiting MMPs therefore may be a mechanism that may be used to control of fertility. In addition, increasing and maintaining the levels of an endogenous or administered serine protease inhibitor (e.g., xcex11-PI) supports the treatment and prevention of pathological conditions such as emphysema, pulmonary diseases, inflammatory diseases, and diseases of aging (e.g., loss of skin or organ stretch and resiliency).
Numerous metalloproteinase inhibitors are known. See, generally, Brown, P.D., xe2x80x9cSynthetic Inhibitors of Matrix Metalloproteinases,xe2x80x9d in Matrix Metalloproteinases, pp. 243-61 (Edited by Parks, W. C. and Mecham, R. P., Academic Press, San Diego, Calif. 1998).
Metalloproteinase inhibitors include, for example, natural biochemicals, such as tissue inhibitor of metalloproteinase (TIMP), xcex12-macroglobulin, and their analogs and derivatives. These are high-molecular-weight protein molecules that form inactive complexes with metalloproteinases.
A number of smaller peptide-like compounds also have been reported to inhibit metalloproteinases. Mercaptoamide peptidyl derivatives, for example, have been reported to inhibit angiotensin converting enzyme (also known as ACE) in vitro and in vivo. ACE aids in the production of angiotensin II, a potent pressor substance in mammals. Inhibiting ACE leads to lowering of blood pressure.
A wide variety of thiol compounds have been reported to inhibit MMPs. See, e.g., WO95/12389. See also, WO96/11209. See also, U.S. Pat. No. 4,595,700. See also, U.S. Pat. No. 6,013,649.
A wide variety of hydroxamate compounds also have been reported to inhibit MMP""s. Such compounds reportedly include hydroxamates having a carbon backbone. See, e.g., WIPO Int""l Pub. No. WO 95/29892. See also, WIPO Int""l Pub. No. WO 97/24117. See also, WIPO Int""l Pub. No. WO 97/49679. See also, European Patent No. EP 0 780 386. Such compounds also reportedly include hydroxamates having peptidyl backbones or peptidomimetic backbones. See, e.g, WIPO Int""l Pub. No. WO 90/05719. See also, WIPO Int""l Pub. No. WO 93/20047. See also, WIPO Int""l Pub. No. WO 95/09841. See also, WIPO Int""l Pub. No. WO 96/06074. See also, Schwartz et al., Progr. Med. Chem., 29:271-334(1992). See also, Rasmussen et al., PharmacoL Ther., 75(1): 69-75 (1997). See also, Denis et al., Invest New Drugs, 15(3): 175-185 (1997). Various piperazinylsulfonylmethyl hydroxamates and piperidinylsulfonylmethyl hydroxamates have additionally been reported to inhibit MMPs. See, WIPO Int""l Pub. No. WO 00/46221. And various aromatic sulfone hydroxamates have been reported to inhibit MMPs. See, WIPO Int""l Pub. No. WO 99/25687. See also, WIPO Int""l Pub. No. WO 00/50396. See also, WIPO Int""l Pub. No. WO 00/69821.
It is often advantageous for an MMP inhibitor drug to target a certain MMP(s) over another MMP(s). For example, it is typically preferred to inhibit MMP-2, MMP-3, MMP-9, and/or MMP-13 (particularly MMP-13) when treating and/or preventing cancer, inhibiting of metastasis, and inhibiting angiogenesis. It also is typically preferred to inhibit MMP-13 when preventing and/or treating osteoarthritis. See, e.g., Mitchell et al., J Clin. Invest., 97:761-768 (1996). See also, Reboul et al., J Clin. Invest., 97:2011-2019 (1996). Normally, however, it is preferred to use a drug that has little or no inhibitory effect on MMP-1 and MMP-14. This preference stems from the fact that both MMP-1 and MMP-14 are involved in several homeostatic processes, and inhibition of MMP-1 and/or MMP-14 consequently tends to interfere with such processes.
Many known MMP inhibitors exhibit the same or similar inhibitory effects against each of the MMPs. For example, batimastat (a peptidomimetic hydroxamate) has been reported to exhibit IC50 values of from about 1 to about 20 nM against each of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9. Marimastat (another peptidomimetic hydroxamate) has been reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum similar to batimastat, except that Marimastat reportedly exhibited an IC50 value against MMP-3 of 230 nM. See Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997).
Meta analysis of data from Phase I/II studies using Marimastat in patients with advanced, rapidly progressive, treatment-refractory solid tumor cancers (colorectal, pancreatic, ovarian, and prostate) indicated a dose-related reduction in the rise of cancer-specific antigens used as surrogate markers for biological activity. Although Marimastat exhibited some measure of efficacy via these markers, toxic side effects reportedly were observed. The most common drug-related toxicity of Marimastat in those clinical trials was musculoskeletal pain and stiffness, often commencing in the small joints in the hands, and then spreading to the arms and shoulder. A short dosing holiday of 1-3 weeks-followed by dosage reduction reportedly permits treatment to continue. See Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997). It is thought that the lack of specificity of inhibitory effect among the MMPs may be the cause of that effect.
Another enzyme implicated in pathological conditions associated with excessive degradation of connective tissue is aggrecanase, particularly aggrecanase-1 (also known as ADAMTSA-4). Specifically, articular cartilage contains large amounts of the proteoglycan aggrecan. Proteoglycan aggrecan provides mechanical properties that help articular cartilage in withstanding compressive deformation during joint articulation. The loss of aggrecan fragments and their release into synovial fluid caused by proteolytic cleavages is a central pathophysiological event in osteoarthritis and rheumatoid arthritis. It has been reported that two major cleavage sites exist in the proteolytically sensitive interglobular domains at the N-terminal region of the aggrecan core protein. One of those sites has been reported to be cleaved by several matrix metalloproteases. The other site, however, has been reported to be cleaved by aggrecanase-1. Thus, inhibiting excessive aggrecanase activity provides an additional and/or alternative prevention or treatment method for inflammatory conditions. See generally, Tang, B. L., xe2x80x9cADAMTS: A Novel Family of Extracellular Matrix Proteases,xe2x80x9d Int""l Journal of Biochemistry and Cell Biology, 33, pp. 33-44 (2001). Such diseases reportedly include, for example, osteoarthritis, rheumatoid arthritis, joint injury, reactive arthritis, acute pyrophosphate arthritis, and psoriatic arthritis. See, e.g., European Patent Application Publ. No. EP 1 081 137 A1.
In addition to inflammatory conditions, there also is evidence that inhibiting aggrecanase may be used for preventing or treating cancer. For example, excessive levels of aggrecanase-1 reportedly have been observed with a ghoma cell line. It also has been postulated that the enzymatic nature of aggrecanase and its similarities with the MPs would support tumor invasion, metastasis, and angiogenesis. See Tang, Int""l Journal of Biochemistry and Cell Biology, 33, pp. 33-44 (2001).
Various hydroxamate compounds have been reported to inhibit aggrecanase-1. Such compounds include, for example, those described in European Patent Application Publ. No. EP 1 081 137 A1. Such compounds also include, for example, those described in WIPO PCT Int""l Publ. No. WO 00/09000. Such compounds further include, for example, those described in WIPO PCT Int""l Publ. No. WO 00/59874.
In view of the importance of hydroxamate compounds in the prevention or treatment of several pathological conditions and the lack of enzyme specificity exhibited by two of the more potent MMP-inhibitor drugs that have been in clinical trials, there continues to be a need for hydroxamates having greater enzyme specificity (preferably toward MMP-2, MMP-9, MMP-13, and/or aggrecanase (particularly toward MMP-13 in some instances, toward both MMP-2 and MMP-9 in other instances, and aggrecanase in yet other instances), while exhibiting little or no inhibition of MMP-1 and/or MMP-14. The following disclosure describes hydroxamate compounds that tend to exhibit such desirable activities.
This invention is directed to hydroxamate compounds (and salts thereof) that inhibit pathological protease activity (particularly compounds that inhibit MMP-2, MMP-9, MMP-13, and/or aggrecanase activity), while generally exhibiting relatively little or no inhibition against MMP-1 and MMP-14 activity. This invention also is directed to a method for inhibiting MMP activity and/or aggrecanase activity, particularly pathological MMP and/or aggrecanase activity. Such a method is particularly suitable to be used with mammals, such as humans, other primates (e.g., monkeys, chimpanzees. etc.), companion animals (e.g., dogs, cats, horses. etc.), farm animals (e.g. goats, sheep, pigs, cattle, etc.), laboratory animals (e.g., mice, rats, etc.), and wild and zoo animals (e.g., wolves, bears, deer, etc.).
Briefly, therefore, the invention is directed in part to a compound or salt thereof. The compound has a structure corresponding to Formula I: 
Here:
A1 is xe2x80x94H, alkylcarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, carbocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, aminoalkylcarbonyl, alkyl(thiocarbonyl), alkoxy(thiocarbonyl), carbocyclyl(thiocarbonyl), carbocyclylalkyl(thiocarbonyl), heterocyclyl(thiocarbonyl), heterocyclylalkyl(thiocarbonyl), carbocyclyloxy(thiocarbonyl), carbocyclylalkoxy(thiocarbonyl), or aminoalkyl(thiocarbonyl). Except where A1 is xe2x80x94H, any member of this group optionally is substituted (i.e., it may be either unsubstituted or substituted).
A2 and A3, together with the carbon atom to which they are both attached, form an optionally-substituted heterocyclyl containing from 5 to 8 ring members.
In a preferred embodiment of the invention, X is xe2x80x94E1xe2x80x94E2xe2x80x94E3xe2x80x94E4xe2x80x94E5. In this embodiment:
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 forms a link of at least 2 carbon atoms between E1 and E3. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
E3 is xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94(CO)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(NR3)xe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R4)xe2x80x94, xe2x80x94N(4)xe2x80x94C(O)xe2x80x94, xe2x80x94N(R4)xe2x80x94C(O)xe2x80x94N(R5)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R4)xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94N(R4)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R4)xe2x80x94N(R5)xe2x80x94C(O)xe2x80x94, xe2x80x94C(R4)(R6)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R7)(R8)xe2x80x94.
E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.
E5 is xe2x80x94H, xe2x80x94OH, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Except where E5 is except xe2x80x94H or xe2x80x94OH, any member of this group optionally is substituted. E5 is not xe2x80x94H when both E3 is xe2x80x94C(R7)(R8)xe2x80x94 and E4 is a bond.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E3, E4, or E5.
R3 is xe2x80x94H or xe2x80x94OH.
R4 and R5 are independently selected from the group consisting of xe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except for xe2x80x94H, any member of this group optionally is substituted. Neither R4 nor R5 forms a ring structure with E2, E4, or E5.
R6 is xe2x80x94CN or xe2x80x94OH.
R7 is xe2x80x94H, halogen, xe2x80x94OH, alkyl, alkoxy, or alkoxyalkyl. The alkyl, alkoxy, and alkoxyalkyl optionally are substituted.
R8 is xe2x80x94OH or alkoxy. The alkoxy optionally is substituted.
In another preferred embodiment of the invention, X is xe2x80x94E1xe2x80x94E2xe2x80x94E3xe2x80x94E4xe2x80x94E5. In this embodiment:
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R1), xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R2)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 forms a link of at least 2 carbon atoms between E1 and E3. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
E3 is carbocyclyl or heterocyclyl. The carbocyclyl and heterocyclyl have 5 or 6 ring members and optionally are substituted.
E4 is a bond, alkyl, alkenyl, xe2x80x94Oxe2x80x94, or xe2x80x94N(R3)xe2x80x94. The alkyl and alkenyl optionally are substituted.
E5 is carbocyclyl or heterocyclyl. The carbocyclyl and heterocyclyl optionally are substituted.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E3, E4, or E5.
R3 is xe2x80x94H or alkyl. The alkyl optionally is substituted.
In another preferred embodiment of the invention, X is xe2x80x94E1xe2x80x94E2xe2x80x94C(E6)xe2x95x90C(7)xe2x80x94E3xe2x80x94E4xe2x80x94E5. In this embodiment:
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
E4 is a bond or alkyl. The alkyl optionally is substituted.
E5 is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
E6 is xe2x80x94H, halogen, or alkyl. The alkyl optionally is substituted.
E7 is xe2x80x94H, alkyl, alkenyl, alkynyl, xe2x80x94S(O)2xe2x80x94R3, xe2x80x94NO2, xe2x80x94C(O)xe2x80x94N(R3)(R4), xe2x80x94(C)(OR3), carbocyclyl, carbocyclylalkyl, alkoxycarbocyclyl, xe2x80x94CN, xe2x80x94Cxe2x95x90Nxe2x80x94OH, or xe2x80x94Cxe2x95x90NH. The alkyl, alkenyl, alkynyl, carbocyclyl, carbocycylalkyl, and alkoxycarbocyclyl optionally are substituted.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E4, E5, E6, or E7.
R3 and R4 are independently selected from the group consisting of xe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted.
In another preferred embodiment of the invention, X is xe2x80x94E1xe2x80x94E2xe2x80x94E3xe2x80x94E4xe2x80x94E5. In this embodiment:
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R3)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R3)xe2x80x94, xe2x80x94N(R3)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 is a bond, alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Except where the member is a bond, any member of such group optionally is substituted.
E3 is carbonylpyrrollidinyl. The carbonylpyrrollidinyl optionally is substituted.
E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally and substituted.
E5 is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E3, E4, or E5.
In another preferred embodiment of the invention, X is xe2x80x94E1xe2x80x94E2xe2x80x94E5. In this embodiment:
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, and haloalkyl.
E5 is alkyl, alkenyl, alkynyl, cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, or cyclohexadienyl. The cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclobexadienyl optionally are substituted. The alkyl, alkenyl, and alkynyl (a) contain at least 4 carbon atoms, and (b) optionally are substituted with one or more substituents selected from the group consisting of xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, and halogen.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E5.
In another preferred embodiment of the invention, X is xe2x80x94E1xe2x80x94E2xe2x80x94E3xe2x80x94E4xe2x80x94E5. In this embodiment:
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
E3 is carbonylpiperidinyl. The carbonylpiperidinyl optionally is substituted.
E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.
E5 is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E3, E4, or E5.
In another preferred embodiment of the invention, X is xe2x80x94E1xe2x80x94E2xe2x80x94E5. In this embodiment:
E1is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 forms a link of at least 3 carbon atoms between E1 and E5. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
E5 is optionally-substituted heterocyclyl, optionally-substituted fused-ring carbocyclyl, or substituted single-ring carbocyclyl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E5.
In another preferred embodiment of the invention, X is xe2x80x94E1xe2x80x94E2xe2x80x94E5. In this embodiment:
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2).
E2 forms a link of at least 4 carbon atoms between E1 and E5. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
E5 is xe2x80x94OH or optionally-substituted carbocyclyl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E5.
In another preferred embodiment of the invention, X is xe2x80x94E1xe2x80x94E2xe2x80x94Oxe2x80x94E4xe2x80x94E5. In this embodiment:
E1 is xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.
E5 is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E4, or E5.
In another preferred embodiment of the invention, X is xe2x80x94Oxe2x80x94E2xe2x80x94Oxe2x80x94E5. In this embodiment:
E2 comprises at least 3 carbon atoms. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
E5 is xe2x80x94H, alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, carbocyclylalkoxyalkyl, heterocyclyl, heterocyclylalkyl, or heterocyclylalkoxyalkyl. The alkyl, alkenyl, alkynyl, and alkoxyalkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN, the carbocyclyl, carbocyclylalkoxyalkyl, heterocyclyl, heterocyclylalkyl, and heterocyclylalkoxyalkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, halogen-substituted alkoxyalkyl, xe2x80x94N(R3)(R4), xe2x80x94C(O)(5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
R3 is xe2x80x94H, alkyl, xe2x80x94Oxe2x80x94R4, xe2x80x94N(R4)(R5), carbocyclylalkyl, or heterocyclylalkyl. The alkyl, carbocyclylalkyl, and heterocyclylalkyl optionally are substituted with one or more halogen.
R4 and R5 are independently selected from the group consisting of xe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
In another preferred embodiment of the invention, X is xe2x80x94Oxe2x80x94E2xe2x80x94Oxe2x80x94E4xe2x80x94E5. In this embodiment:
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted. An atom in E2optionally is bound to an atom in E5 to form a ring.
E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.
E5 is:
an optionally-substituted radical selected from the group consisting of alkenyl, alkynyl, alkoxy, alkoxyalkyl, fused-ring carbocyclyl, and heterocyclyl;
single-ring carbocyclyl substituted with one or more substituents independently selected from the group consisting of xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, halogen-substituted carbocyclylalkyl, heterocyclyl, haloheterocyclyl, heterocyclylalkyl, and halogen-substituted heterocyclylalkyl; or
single-ring carbocyclyl having multiple substitutions.
R1 and R2 are independently selected from the group consisting of xe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
R3 is xe2x80x94H, alkyl, xe2x80x94Oxe2x80x94R4, xe2x80x94N(R4)(R5), carbocyclylalkyl, or heterocyclylalkyl. The alkyl, carbocyclylalkyl, and heterocyclylalkyl optionally are substituted with one or more halogen.
R4 and R5 are independently selected from the group consisting ofxe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
In another preferred embodiment of the invention, X is xe2x80x94E1xe2x80x94E2xe2x80x94S(O)2xe2x80x94E4xe2x80x94E5. In this embodiment:
E1 is xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.
E5 is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E4, or E5.
In another preferred embodiment of the invention, X is xe2x80x94Oxe2x80x94E2xe2x80x94S(O)2xe2x80x94E4xe2x80x94E5. In this embodiment:
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
E4 is alkyl or alkenyl. The alkyl and alkenyl optionally are substituted.
E5 is xe2x80x94H, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
In another preferred embodiment of the invention, X is xe2x80x94Oxe2x80x94E2xe2x80x94S(O)2xe2x80x94E5. In this embodiment:
E2 comprises less than 5 carbon atoms. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
E5 is alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
In another preferred embodiment of the invention, X is xe2x80x94Oxe2x80x94E2xe2x80x94S(O)2xe2x80x94E5. In this embodiment:
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
E5 is alkyl, alkenyl, alkynyl, alkoxyalkyl, saturated carbocyclyl, partially saturated carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
In another preferred embodiment of the invention, X is: 
In this embodiment:
E1xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O), or xe2x80x94C(R)(R2)xe2x80x94.
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
E4 is a bond, alkyl, or alkenyl, The alkyl and alkenyl optionally are substituted.
E5 is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E4, or E5.
In another preferred embodiment of the invention, X is: 
In this embodiment:
E2 is a bond, alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.
E5 is substituted carbocyclyl or optionally-substituted heterocyclyl. The carbocyclyl is substituted with:
two or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, halogen-substituted alkoxyalkyl, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl; or
a substituent selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)Oxe2x80x94R3, xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl.
The heterocyclyl, on the other hand, optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, halogen-substituted alkoxyalkyl, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl.
R3 and R4 are independently selected from the group consisting of xe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
R5 is xe2x80x94H, alkyl, xe2x80x94Oxe2x80x94R6, xe2x80x94N(R6)(R7), carbocyclylalkyl, or heterocyclylalkyl. The alkyl, carbocyclylalkyl, and heterocyclylalkyl optionally are substituted with one or more halogen.
R6 and R7 are independently selected from the group consisting of xe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
In another preferred embodiment of the invention, X is xe2x80x94E1xe2x80x94E2xe2x80x94E5. In this embodiment:
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(ON(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E1 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of such group optionally is substituted.
E5 is substituted heterocyclyl.
R1 and R2 are independently selected from the group consisting ofxe2x80x94H and alkyl. The alkyl optionally is substituted.
Neither R1 nor R2 forms a ring structure with E5.
In another preferred embodiment of the invention, X is xe2x80x94E1xe2x80x94E2xe2x80x94E5. In this embodiment:
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of such group optionally is substituted. In addition, E2 comprises at least two carbon atoms.
E5 is optionally-substituted heterocyclyl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substitute.
Neither R1 nor R2 forms a ring structure with E5.
In another preferred embodiment of the invention, X is xe2x80x94E1xe2x80x94E2xe2x80x94E3xe2x80x94E4xe2x80x94E5. In this embodiment:
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of such group optionally is substituted.
E3 is xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94(CO)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(NR3)xe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x80x94N(R4)xe2x80x94C(NR3)xe2x80x94, xe2x80x94C(NR3)xe2x80x94N(R4)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R4)xe2x80x94, xe2x80x94N(R4)xe2x80x94C(O)xe2x80x94, xe2x80x94N(R4)xe2x80x94C(O)xe2x80x94N(R5)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R4)xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94N(R4)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R4)xe2x80x94N(R5)xe2x80x94C(O)xe2x80x94, xe2x80x94C(R4)(R6)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R7)(R8)xe2x80x94.
E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.
E5 is carbocyclyl or heterocyclyl. The carbocyclyl and heterocyclyl are:
substituted with a substituent selected from the group consisting of optionally-substituted carbocyclyl, optionally-substituted carbocyclylalkyl, optionally-substituted heterocyclyl, and optionally-substituted heterocyclylalkyl; and
optionally substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, alkyl, alkoxy, alkoxyalkyl, xe2x80x94N(R11)(R12), xe2x80x94C(O)(R13), xe2x80x94Sxe2x80x94R11, xe2x80x94S(O)2xe2x80x94R11, carbocyclyl, carbocyclylalkyl, haloalkyl, haloalkoxy, halogen-substituted alkoxyalkyl, halocarbocyclyl, halogen-substituted carbocyclylalkyl, hydroxycarbocyclyl, and heteroaryl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl, wherein the alkyl optionally is substituted.
R3 is xe2x80x94H or xe2x80x94OH.
R4 and R5 are independently selected from the group consisting of xe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl, wherein any member (except xe2x80x94H) of such group optionally is substituted.
R6 is xe2x80x94CN or xe2x80x94OH.
R7 is xe2x80x94H, halogen, xe2x80x94OH, alkyl, alkoxy, or alkoxyalkyl. The alkyl, alkoxy, and alkoxyalkyl optionally are substituted.
R8 is xe2x80x94OH or alkoxy. The alkoxy optionally is substituted.
R11 and R12 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Any member (except xe2x80x94H) of such group optionally is substituted with one or more halogen.
R13 is xe2x80x94H, C1-C8-alkyl, xe2x80x94Oxe2x80x94R14, xe2x80x94N(R14)(R15), carbocyclyl-C1-C8-alkyl, heterocyclyl-C1-C8-alkyl, halo-C1-C8-alkyl, halogen-substituted carbocyclyl-C1-C8-alkyl, or halogen-substituted heterocyclyl-C1-C8-alkyl.
R14 and R15 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Any member (except xe2x80x94H) of such group optionally is substituted with one or more halogen.
Neither R1 nor R2 forms a ring structure with E2, E3, E4, or E5.
Neither R4 nor R5 forms a ring structure with E2, E3, E4, or E5.
This invention also is directed, in part, to a method for preventing or treating a condition associated with pathological matrix metalloprotease activity in a mammal having the condition or predisposed to having the condition. The method comprises administering an above-described compound or a pharmaceutically acceptable salt thereof to the mammal in an amount that is therapeutically-effective to prevent or treat the condition.
This invention also is directed, in part, to a method for preventing or treating a pathological condition in a mammal having the condition or predisposed to having the condition. The method comprises administering an above-described compound or a pharmaceutically acceptable salt thereof to the mammal in an amount that is therapeutically-effective to prevent or treat the condition. In this embodiment, the pathological condition comprises tissue destruction, a fibrotic disease, pathological matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a kidney disease, a liver disease, an ophthalmologic disease, and a central nervous system disease.
This invention also is directed, in part, to a method for preventing or treating a pathological condition in a mammal having the condition or predisposed to having the condition. The method comprises administering an above-described compound or a pharmaceutically acceptable salt thereof to the mammal in an amount that is therapeutically-effective to prevent or treat the condition. In this embodiment, the pathological condition comprises osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion, tumor metastasis, tumor angiogenesis, a decubitis ulcer, a gastric ulcer, a corneal ulcer, periodontal disease, liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis, multiple sclerosis, dilated cardiomyopathy, epidermal ulceration, epidermolysis bullosa, aortic aneurysm, defective injury repair, an adhesion, scarring, congestive heart failure, post myocardial infarction, coronary thrombosis, emphysema, proteinuria, Alzheimer""s disease, bone disease, and chronic obstructive pulmonary disease.
This invention also is directed, in part, to a method for preventing or treating a condition associated with pathological TNF-xcex1 convertase activity in a mammal having the condition or predisposed to having the condition. The method comprises administering an above-described compound or a pharmaceutically acceptable salt thereof to the mammal in an amount that is therapeutically-effective to prevent or treat the condition.
This invention also is directed, in part, to a method for preventing or treating a condition associated with pathological aggrecanase activity in a mammal having the condition or predisposed to having the condition. The method comprises administering an above-described compound or a pharmaceutically acceptable salt thereof to the mammal in an amount that is therapeutically-effective to prevent or treat the condition.
This invention also is directed, in part, to pharmaceutical compositions comprising a therapeutically-effective amount of an above-described compound or a pharmaceutically-acceptable salt thereof.
This invention also is directed, in part, to a use of an above-described compound or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a condition associated with pathological matrix metalloprotease activity.
This invention also is directed, in part, to a use of an above-described compound or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a condition associated with pathological TNF-xcex1 convertase activity.
This invention also is directed, in part, to a use of an above-described compound or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a condition associated with pathological aggrecanase activity.
Further benefits of Applicants"" invention will be apparent to one skilled in the art from reading this patent.
This detailed description of preferred embodiments is intended only to acquaint others skilled in the art with Applicants"" invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This detailed description and its specific examples, while indicating preferred embodiments of this invention, are intended for purposes of illustration only. This invention, therefore, is not limited to the preferred embodiments described in this patent, and may be variously modified.
In accordance with this invention, it has been found that certain aromatic sulfone hydroxamates tend to be effective for inhibiting MMPs, particularly those associated with excessive (or otherwise pathological) breakdown of connective tissue. Specifically, Applicants have found that these hydroxamates tend to be effective for inhibiting proteases (particularly MMP-2, MMP-9, MMP-13, other MMP""s associated with pathological conditions, and/or aggrecanase) that are often particularly destructive to tissue if present or generated in abnormally excessive quantities or concentrations. Moreover, Applicants have discovered that these hydroxamates tend to be selective toward inhibiting pathological protease activity, while avoiding excessive inhibition of other proteases (particularly MMP-1 and/or MMP-14) that are typically essential to normal bodily function (e.g., tissue turnover and repair).
As noted above, the compound of this invention generally has a structure corresponding to Formula I: 
A1 is xe2x80x94H, alkylcarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, carbocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, aminoalkylcarbonyl, alkyl(thiocarbonyl), alkoxy(thiocarbonyl), carbocyclyl(thiocarbonyl), carbocyclylalkyl(thiocarbonyl), heterocyclyl(thiocarbonyl), heterocyclylalkyl(thiocarbonyl), carbocyclyloxy(thiocarbonyl), carbocyclylalkoxy(thiocarbonyl), or aminoalkyl(thiocarbonyl). Except where the member is xe2x80x94H, any member of this group optionally is substituted.
In some preferred embodiments, A1 is xe2x80x94H, C1-C8-alkylcarbonyl, C1-C8-alkoxycarbonyl, carbocyclylcarbonyl, carbocyclyl-C1-C8-alkylcarbonyl, heterocyclylcarbonyl, heterocyclyl-C1-C8-alkylcarbonyl, carbocyclyloxycarbonyl, carbocyclyl-C1-C8-alkoxycarbonyl, N(RA)(RB)xe2x80x94C1-C8-alkylcarbonyl, C1-C8-alkyl(thiocarbonyl), C1-C8-alkoxy(thiocarbonyl), carbocyclyl(thiocarbonyl), carbocyclyl-C1-C8-alkyl(thiocarbonyl), heterocyclyl(thiocarbonyl), heterocyclyl-C1-C8-alkyl(thiocarbonyl), carbocyclyloxy(thiocarbonyl), carbocyclyl-C1-C8-alkoxy(thiocarbonyl), or N(RA)(RB)xe2x80x94C1-C8-alkyl(thiocarbonyl). RA and RB are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, C1-C8-alkoxycarbonyl, C1-C8-alkylcarbonyl, carbocyclyl-C1-C8-alkyl, and carbocyclyl-C1-C8-alkoxycarbonyl.
In generally more preferred embodiments, A1 is xe2x80x94H.
A2 and A3, together with the carbon atom to which they are both attached, form an optionally-substituted heterocyclyl containing from 5 to 8 ring members (i.e., from 5 to 8 atoms are bound together to form the ring (or rings) of the heterocyclyl).
In some preferred embodiments, A2 and A3, together with the carbon atom to which they both are attached, form an optionally-substituted heterocyclyl containing either 5 or 6 ring members.
In some preferred embodiments, the compound corresponds in structure to one of the following formulas: 
A4 is xe2x80x94H, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonylalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkylcarbonyl, alkylsulfonyl, alkyliminocarbonyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, alkylsulfoxidoalkyl, alkylthioalkenyl, alkylsulfoxidoalkenyl, alkylsulfonylalkenyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkoxyalkyl, carbocyclylcarbonyl, carbocyclylsulfonyl, carbocyclyliminocarbonyl, carbocyclyloxycarbonyl, carbocyclylthioalkyl, carbocyclylsulfoxidoalkyl, carbocyclylsulfonylalkyl, carbocyclylthioalkenyl, carbocyclylsulfoxidoalkenyl, carbocyclylsulfonylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxyalkyl, heterocyclylcarbonyl, heterocyclylthioalkyl, heterocyclylsulfoxidoalkyl, heterocyclylsulfonylalkyl, heterocyclylthioalkenyl, heterocyclylsulfoxidoalkenyl, heterocyclylsulfonylalkenyl, heterocyclylsulfonyl, heterocyclyliminocarbonyl, heterocyclylalkylcarbonyl, heterocyclylcarbonylalkylcarbonyl, heterocyclylsulfonyl, heterocyclylcarbonylalkyl, aminoalkylcarbonyl, aminocarbonyl, aminocarbonylalkylcarbonyl, aminosulfonyl, aminosulfonylalkyl, aminoalkyl, aminocarbonylalkyl, or aminoalkylsulfonyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted.
In some preferred embodiments, A4 is xe2x80x94H, C1-C8-alkyl, C1-C8-alkylcarbonyl, C1-C8-alkylcarbonyl-C1-C8-alkyl, C1-C8-alkylcarbonyl-C1-C8-alkylcarbonyl, C1-C8-alkoxycarbonyl, C1-C8-alkoxycarbonyl-C1-C8-alkyl, C1-C8-alkoxycarbonyl-C1-C8-alkylcarbonyl, C1-C8-alkylsulfonyl, C1-C8-alkylaminocarbonyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy-C1-C8-alkyl, C1-C8-alkylthio-C1-C8-alkyl, C1-C8-alkylthio-C2-C8-alkenyl, C1-C8-alkylsulfoxido-C1-C8-alkyl, C1-C8-alkylsulfoxido-C2-C8-alkenyl, C1-C8-alkylsulfonyl-C1-C8-alkyl, C1-C8-alkylsulfonyl-C2-C8-alkenyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, carbocyclyl-C1-C8-alkoxy-C1-C8-alkyl, carbocyclylcarbonyl, carbocyclylsulfonyl, carbocyclyliminocarbonyl, carbocyclyloxycarbonyl, carbocyclylthio-C1-C8-alkyl, carbocyclylthio-C2-C8-alkenyl, carbocyclylsulfoxido-C1-C8-alkyl, carbocyclylsulfoxido-C2-C8-alkenyl, carbocyclylsulfonyl-C1-C8-alkyl, carbocyclylsulfonyl-C2-C8-alkenyl, heterocyclyl, heterocyclyl-C1-C8-alkyl, heterocyclyl-C1-C8-alkoxy-C1-C8-alkyl, heterocyclylcarbonyl, heterocyclylthio-C1-C8-alkyl, heterocyclylsulfoxido-C1-C8-alkyl, heterocyclylsulfonyl-C1-C8-alkyl, heterocyclylthio-C2-C8-alkenyl, heterocyclylsulfoxido-C2-C8-alkenyl, heterocyclylsulfonyl-C2-C8-alkenyl, heterocyclylsulfonyl, heterocyclyliminocarbonyl, heterocyclyl-C1-C8-alkylcarbonyl, heterocyclylcarbonyl-C1-C8-alkylcarbonyl, heterocyclylsulfonyl, heterocyclylcarbonyl-C1-C8-alkyl, N(RC)(RD)xe2x80x94C1-C8-alkylcarbonyl, N(RC)(RD)-carbonyl, N(RC)(RD)-carbonyl-C1-C8-alkylcarbonyl, N(RC)(RD)-sulfonyl, N(RC)(RD)-sulfonyl-C1-C8-alkyl, N(RC)(RD)xe2x80x94C1-C8-alkyl, N(RC)(RD)carbonyl-C1-C-alkyl, or N(RC)(RD)xe2x80x94C1-C8-alkylsulfonyl. Any substitutable member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94CN, xe2x80x94C(O)xe2x80x94OH, xe2x80x94SH, xe2x80x94SO3H, and NO2.
RC and RD are independently selected from the group consisting of xe2x80x94H, xe2x80x94OH, C1-C8-alkyl, C1-C8-alkyl-carbonyl, C1-C8-alkoxy-C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkyl-thio-C1-C8-alkyl, C1-C8-alkyl-sulfoxido-C1-C8-alkyl, C1-C8-alkyl-sulfonyl-C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, carbocyclylcarbonyl, carbocyclyl-C1-C8-alkoxy-C1-C8-alkyl, carbocyclylthio-C1-C8-alkyl, carbocyclylsulfoxido-C1-C8-alkyl, carbocyclylsulfonyl-C1-C8-alkyl, heterocyclyl, heterocyclyl-C1-C8-alkyl, heterocyclyl-C1-C8-alkoxy-C1-C8-alkyl, heterocyclylcarbonyl, heterocyclylthio-C1-C8-alkyl, heterocyclylsulfoxido-C1-C8-alkyl, heterocyclylsulfonyl-C1-C8-alkyl, aminocarbonyl-C1-C8-alkyl, C1-C8-alkyloxycarbonylamino-C1-C8-alkyl, and amino-C1-C8-alkyl. Except where the member is xe2x80x94H or OH, any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94CN, xe2x80x94C(O)xe2x80x94OH, xe2x80x94SH, xe2x80x94SO3H, and NO2. The nitrogen of the amino-C1-C8-alkyl optionally is substituted with 1 or 2 substituents independently selected from the group consisting of C1-C8-alkyl, C1-C8-alkylcarbonyl, carbocyclyl, and carbocyclyl-C1-C8-alkyl. No greater than one of RC or RD is xe2x80x94OH.
In some preferred embodiments, A4 is xe2x80x94H, C1-C6-alkyl (often preferably C1-C4-alkyl, and more preferably ethyl), C1-C6-alkoxy-C1-C6-alkyl (often preferably C1-C2-alkoxy-C1-C3-alkyl, and more preferably methoxyethyl), carbocyclyl (often preferably C3-C6-cycloalkyl or phenyl, and more preferably cyclopropyl), carbocyclyl-C1-C6-alkyl (often preferably C3-C6-cycloalkyl-C1-C3-alkyl or phenyl-C1-C3-alkyl, and more preferably cyclopropylmethyl or benzyl), C1-C6-alkylsulfonyl (often preferably C1-C2-alkylsulfonyl, and more preferably methylsulfonyl), C3-C6-alkenyl (often preferably C3-C4-alkenyl, and more preferably C3-alkenyl), C3-C6-alkynyl (often preferably C3-C4-alkynyl, and more preferably C3-alkynyl). Except where the member is xe2x80x94H, any member of these groups optionally is substituted with halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, A4 is xe2x80x94H, ethyl, methoxyethyl, cyclopropyl, cyclopropylmethyl, or benzyl.
X may be selected from a wide range of substituents. The following discussion describes several specific preferred embodiments encompassing the substituents that Applicants have found to be generally preferred.
In some embodiments of this invention, the compound has a structure corresponding to Formula II: 
A1, A2, and A3 are as defined above for Formula I.
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O), xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94. E1 alternatively may be xe2x80x94Sxe2x80x94.
E2 forms a link of at least 2 carbon atoms between E1 and E3. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
In some preferred embodiments, E2 is C2-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, E2 is C2-C6-alkyl optionally substituted with one or more halogen.
In some preferred embodiments, E2 is C2-C6-alkyl.
In some preferred embodiments, E2 is C2-C6-alkyl.
E3 is xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94(CO)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(NR3)xe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R4)xe2x80x94, xe2x80x94N(R4)xe2x80x94C(O)xe2x80x94, xe2x80x94N(R4)xe2x80x94C(O)xe2x80x94N(R5)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R4)xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94N(R4)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R4)xe2x80x94N(R5)xe2x80x94C(O)xe2x80x94, xe2x80x94C(R4)(R6)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R7)(R8)xe2x80x94.
E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.
In some preferred embodiments, E4 is a bond, C1-C20-alkyl, or C2-C20-alkenyl. The C1-C20-alkyl and C2-C20-alkenyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen and carbocyclyl. This carbocyclyl, in turn, optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, halo-C1-C8-alkyl, halo-C1-C8-alkoxy, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, halocarbocyclyl, and halogen-substituted carbocyclyl-C1-C8-alkyl.
In some preferred embodiments, E4 a bond, C1-C3-alkyl, or C2-C3-alkenyl. The C1-C3-alkyl, and C2-C3-alkenyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen and carbocyclyl. This carbocyclyl, in turn, optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, halocarbocyclyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.
In some preferred embodiments, E4 is a bond, C1-C3-alkyl, or C2-C3-alkenyl.
E5 is xe2x80x94H, xe2x80x94OH, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Except where E5 is xe2x80x94H or xe2x80x94OH, any member of this group optionally is substituted. E5 is not xe2x80x94H when both E3 is xe2x80x94C(R7)(R8)xe2x80x94 and E4 is a bond.
In some preferred embodiments, E5 is xe2x80x94H, xe2x80x94OH, C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, or heterocyclyl. The C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R11)(R12), xe2x80x94C(O)(R13), xe2x80x94Sxe2x80x94R11, xe2x80x94S(O)2xe2x80x94R11, carbocyclyl, carbocyclyl-C1-C8-alkyl, halo-C1-C8-alkyl, halo-C1-C8-alkoxy, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, halocarbocyclyl, and halogen-substituted carbocyclyl-C1-C8-alkyl. The carbocyclyl and heterocyclyl also optionally are substituted with one or more substituents independently selected from the group consisting of C1-C8-alkylcarbocyclyl, halogen-substituted C1-C8-alkylcarbocyclyl, hydroxycarbocyclyl, and heterocyclyl.
In some preferred embodiments, E5 is xe2x80x94H, xe2x80x94OH, C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, carbocyclyl, or heterocyclyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R11)(R12), xe2x80x94C(O)(R13), xe2x80x94Sxe2x80x94R11, xe2x80x94S(O)2xe2x80x94R11, carbocyclyl, carbocyclyl-C1-C6-alkyl, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, halocarbocyclyl, halogen-substituted carbocyclyl-C1-C6-alkyl, C1-C6-alkylcarbocyclyl, halogen-substituted C1-C6-alkylcarbocyclyl, hydroxycarbocyclyl, and heteroaryl.
In some preferred embodiments, E5 is furanyl, tetrahydropyranyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl, dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, oxazolidinyl, isoxazolidinyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl, dihydropyranyl, pyridinyl, piperidinyl, diazinyl, piperazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, morpholinyl, azepinyl, oxepinyl, thiepinyl, diazepinyl, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofilranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, tetrahydroisoquinolinyl, carbazolyl, xanthenyl, or acridinyl. Such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R11)(R12), xe2x80x94C(O)(R13), xe2x80x94Sxe2x80x94R11, xe2x80x94S(O)2xe2x80x94R11, aryl, aryl-C1-C6-alkyl, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, haloaryl, and halogen-substituted aryl-C1-C6-alkyl. Any member of such group also optionally is substituted with one or more substituent independent selected from the group consisting of C1-C6-alkylaryl, halogen-substituted C1-C6-alkylaryl, hydroxyaryl, and heteroaryl.
In some preferred embodiments, E5 is indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, tetrahydroisoquinolinyl, or pyridofuranyl. Such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R11)(R12), xe2x80x94C(O)(R13), xe2x80x94Sxe2x80x94R11, xe2x80x94S(O)2xe2x80x94R11, aryl, aryl-C1-C6-alkyl, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, haloaryl, halogen-substituted aryl-C1-C6-alkyl. Such substituent also optionally is substituted with one or more substituents independently selected from the group consisting of C1-C6-alkylaryl, halogen-substituted C1-C6-alkylaryl, hydroxyaryl, and heteroaryl.
In some preferred embodiments, E5 is benzazinyl, benzofuranyl, or tetrahydroisoquinolinyl. Such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R11)(R12), xe2x80x94C(O)(R13), xe2x80x94Sxe2x80x94R11, xe2x80x94S(O)2xe2x80x94R11, aryl, aryl-C1-C6-alkyl, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, haloaryl, and halogen-substituted aryl-C1-C6-alkyl. Such substituent also optionally is substituted with one or more substituents independently selected from the group consisting of C1-C6-alkylaryl, halogen-substituted C1-C6-alkylaryl, hydroxyaryl, and heteroaryl.
In some preferred embodiments, E5 is indolyl, benzoxazolyl, benzothienyl, benzothiazolyl, or pyridofuranyl. Such substituent any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R11)(R12), xe2x80x94C(O)(R13), xe2x80x94Sxe2x80x94R11, xe2x80x94S(O)2xe2x80x94R11, aryl, aryl-C1-C6-alkyl, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, haloaryl, and halogen-substituted aryl-C1-C6-alkyl. Such substituent also optionally is substituted with one or more substituents independently selected from the group consisting of C1-C6-alkylaryl, halogen-substituted C1-C6-alkylaryl, hydroxyaryl, and heteroaryl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E3, or E5.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, and halo-C1-C8-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, and C1-C6-alkyl.
R3 is xe2x80x94H or xe2x80x94OH.
R4 and R5 are independently selected from the group consisting of xe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except for xe2x80x94H, any member of this group optionally is substituted. Neither R4 nor R5 forms a ring structure with E2, E4, or E5.
In some preferred embodiments, R4 and R5 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R4 and R5 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R6 is xe2x80x94CN or xe2x80x94OH.
R7 is xe2x80x94H, halogen, xe2x80x94OH, alkyl, alkoxy, or alkoxyalkyl. The alkyl, alkoxy, and alkoxyalkyl optionally are substituted.
In some preferred embodiments, R7 is xe2x80x94H, halogen, xe2x80x94OH, C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halo-C1-C8-alkyl, halo-C1-C8-alkoxy, or halogen-substituted C1-C8-alkoxy-C1-C8-alkyl.
In some preferred embodiments, R7 is xe2x80x94H, halogen, xe2x80x94OH, C1-C6-alkyl, C1-C6-alkoxy, C1C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, or halogen-substituted C1-C6-alkoxy-C1-C6-alkyl.
In some preferred embodiments, R7 is xe2x80x94H, halogen, xe2x80x94OH, C1-C6-alkyl, C1-C6-alkoxy, or C1-C6-alkoxy-C1-C6-alkyl.
R8 is xe2x80x94OH or alkoxy. The alkoxy optionally is substituted.
In some preferred embodiments, R8 is xe2x80x94OH, C1-C8-alkoxy, or halo-C1-C8-alkoxy.
In some preferred embodiments, R8 is xe2x80x94OH, C1-C6-alkoxy, or halo-C1-C6-alkoxy.
In some preferred embodiments, R8 is xe2x80x94OH or C1-C6-alkoxy.
R11 and R12 are independently selected from the group consistingof xe2x80x94H. C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R11 and R12 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R13 is xe2x80x94H, C1-C8-alkyl, xe2x80x94Oxe2x80x94R14, xe2x80x94N(R14)(R15), carbocyclyl-C1-C8-alkyl, heterocyclyl-C1-C8-alkyl, halo-C1-C8-alkyl, halogen-substituted carbocyclyl-C1-C8-alkyl, or halogen-substituted heterocyclyl-C1-C8-alkyl.
In some preferred embodiments, R13 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R14, xe2x80x94N(R14)(R15), carbocyclyl-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, halo-C1-C6-alkyl, halogen-substituted carbocyclyl-C1-C6-alkyl, or halogen-substituted heterocyclyl-C1-C6-alkyl.
In some preferred embodiments, R13 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R14, xe2x80x94N(R14)(R15), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl.
R14 and R15 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but typically is preferably not substituted with halogen.
In some preferred embodiments, R14 and R15 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-allyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but typically is preferably not substituted with halogen.
In some embodiments, E3 is xe2x80x94C(O)xe2x80x94.
In some such embodiments, E5 is optionally-substituted carbocyclyl, and often preferably optionally-substituted cycloalkyl or optionally-substituted aryl.
In some preferred embodiments, for example, E5 is optionally-substituted phenyl. Such compounds include, for example: 
Such compounds also include compounds wherein E5 is phenyl substituted with one or more substituents independently selected from the group consisting of aryl, haloaryl, aryl-C1-C6-alkyl, and halogen-substituted aryl-C1-C6-alkyl. Here, the phenyl also optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, N(R11)(R12), xe2x80x94C(O)(R13), xe2x80x94Sxe2x80x94R11, xe2x80x94S(O)2xe2x80x94R11, aryl, aryl-C1-C6-alkyl, halo-C1-6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, haloaryl, halogen-substituted aryl-C1-C6-alkyl, C1-C6-alkylaryl, halogen-substituted C1-C6-alkylaryl, hydroxyaryl, and heteroaryl. Such compounds include, for example: 
In other preferred embodiments, E5 is optionally-substituted naphthalenyl. Such compounds include, for example: 
In yet other preferred embodiments, E5 is optionally-substituted C5-C6-cycloalkyl. Such compounds include, for example: 
In some preferred embodiments, E5 is xe2x80x94H, xe2x80x94OH, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, or C1-C6-alkoxy-C1-C6-alkyl. The C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, and C1-C6-alkoxy-C1-C6-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. Such compounds include, for example: 
Other such compounds include, for example: 
In other preferred embodiments, E5 is optionally-substituted heterocyclyl. In one such embodiment, E5 is optionally-substituted thiophenyl. Such compounds include, for example: 
Other such compounds include, for example: 
In some embodiments, E3 is xe2x80x94Sxe2x80x94.
In some such embodiments, E5 is xe2x80x94H, xe2x80x94OH, C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, or C1-C8-alkoxy-C1-C8-alkyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. Such compounds include, for example: 
In some preferred embodiments, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: 
In some preferred embodiments, E5 is optionally-substituted heterocyclyl. In one such embodiment, E5 is optionally-substituted pyrimidinyl. Such compounds include, for example: 
In another such embodiment, E5 is optionally-substituted 2-fused-ring heterocyclyl. In some preferred embodiments, E5 is optionally-substituted benzoxazolyl or optionally-substituted benzothiazolyl. Such compounds include, for example: 
Other such compounds include, for example: 
In some embodiments, E3 is xe2x80x94N(R4)xe2x80x94C(O)xe2x80x94.
In some such embodiments, E5 is optionally-substituted carbocyclyl. In some preferred embodiments, E5 is optionally-substituted phenyl. Such compounds include, for example: 
Other such compounds include, for example: 
In some preferred embodiments, E5 is optionally-substituted naphthalenyl. Such compounds include, for example: 
In some preferred embodiments, E5 is optionally-substituted cycloalkyl. Such compounds include, for example, fused-ring cycloalkyls. These compounds include, for example: 
These compounds also include, for example: 
In some preferred embodiments, E5 is optionally-substituted C1-C6-cycloalkyl. These compounds include, for example: 
In some preferred embodiments, E5 is optionally-substituted heterocyclyl. In one such embodiment, E5 is an optionally-substituted heterocyclyl selected from the group consisting of pyridinyl, pyrrolyl, isopyrrolyl, oxazolyl, isoxazole, thiazolyl, furanyl, and morphonlinyl. In another such embodiment, E5 is an optionally-substituted heterocylcyl selected from the group consisting of tetrazolyl, imidazolyl, and thienyl. Compounds of these embodiments include, for example: 
Such compounds also include, for example: 
In some preferred embodiments, E5 is optionally-substituted 2-fused-ring heterocyclyl. In some more preferred embodiments, E5 is an optionally-substituted heterocyclyl selected from the group consisting of benzazinyl, benzofuranyl, tetrahydroisoquinolinyl or pyridofuranyl. In some other more preferred embodiments, E5 is an optionally-substituted heterocyclyl selected from the group consisting of indolyl, benzoxazolyl, benzothienyl, and benzothiazolyl. Compounds of such embodiments include, for example: 
Other such compounds include, for example: 
In some preferred embodiments, E5 is xe2x80x94OH, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, or C1-C6-alkoxy-C1-C6-alkyl. Except where the member is xe2x80x94OH, any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. Such compounds include, for example: 
In some embodiments, E3 is xe2x80x94C(O)xe2x80x94N(R14)xe2x80x94.
In some such embodiments, for example, E5is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl.
In some preferred embodiments, E5 is optionally-substituted phenyl. Such compounds include, for example: 
Other such compounds include, for example: 
In some preferred embodiments, E5 is optionally-substituted naphthalenyl. These compounds include, for example: 
In some preferred embodiments, E5 is xe2x80x94OH, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, or C1-C6-alkoxy-C1-C6-alkyl. Except where the member is xe2x80x94OH, any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. Such compounds include, for example: 
In some embodiments, E3 is xe2x80x94N(R4)xe2x80x94C(O)xe2x80x94N(R5)xe2x80x94. In some such embodiments, for example, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: 
In some embodiments, E3 is xe2x80x94S(Oxe2x80x94NR4)xe2x80x94.
In some such embodiments, E5 is optionally-substituted carbocyclyl. The carbocyclyl may be, for example, cycloalkyl. Such compounds include, for example: 
In some preferred embodiments, the carbocyclyl is aryl (preferably phenyl). Such compounds include, for example: 
In some preferred embodiments, E5 is xe2x80x94H, xe2x80x94OH, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, or C1-C6-alkoxy-C1-C6-alkyl. Except where the member is xe2x80x94H or xe2x80x94OH, any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. Such compounds include, for example: 
In some embodiments, E3 is xe2x80x94N(R4)xe2x80x94S(O)2. In some such embodiments, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: 
Other such compounds include, for example: 
In some embodiments, E3 is xe2x80x94C(O)xe2x80x94N(R4)xe2x80x94N(R5)xe2x80x94C(O)xe2x80x94. In some such embodiments, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: 
In some embodiments, E3 is xe2x80x94C(R4)(R6)xe2x80x94C(O)xe2x80x94. In some such embodiments, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: 
In some embodiments, E3 is xe2x80x94C(O)xe2x80x94. In some such embodiments, E5 is optionally-substituted heterocyclyl. In some preferred embodiments, E5is an optionally-substituted 2-fused-ring heterocyclyl. In some embodiments, for example, E5 is optionally-substituted tetrahydroisoquinolinyl . Such compounds include, for example: 
In some embodiments, E3 is xe2x80x94N(R4)xe2x80x94. In some such embodiments, E5 is optionally-substituted heterocyclyl. In some preferred embodiments, E5 is optionally-substituted 2-fused-ring heterocyclyl. In some embodiments, for example, E5 is optionally-substituted benzoxazolyl, benzothiazolyl, or benzimidazolyl. Such compounds include, for example: 
In some embodiments, E3 is xe2x80x94C(NR3)xe2x80x94. In some such embodiments, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: 
In some embodiments, E3 is xe2x80x94C(R7)(R8)xe2x80x94. In some such embodiments, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: 
In some embodiments, E3 is xe2x80x94N(R4)xe2x80x94C(NR3)xe2x80x94. In some such embodiments, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: 
In some embodiments of this invention, the compound has a structure to Formula III: 
A1, A2, and A3 are as defined above for Formula I.
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94. E1 alternatively maybe xe2x80x94Sxe2x80x94.
E2 forms a link of at least 2 carbon atoms between E1 and E3. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
In some preferred embodiments, E2 is C2-C20-alkyl, cycloalkyl, C1-C10-alkylcyloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, E2 is C2-C6-alkyl optionally substituted with one or more halogen.
In some preferred embodiments, E2 is C2-C5-alkyl optionally substituted with one or more halogen.
In some preferred embodiments, E2 is C2-C5-alkyl.
In some preferred embodiments, E2 is xe2x80x94(CH2)mxe2x80x94, wherein m is from 2 to 5.
E3 is carbocyclyl or heterocyclyl. This carbocyclyl and heterocyclyl have 5 or 6 ring members and optionally are substituted.
In some preferred embodiments, E3 is carbocyclyl or heterocyclyl wherein the carbocyclyl and heterocyclyl have 5 or 6 ring members and optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, keto, C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the substituent is halogen, xe2x80x94OH, or keto, any of these substituents optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, C1-C8-alkylthio, halo-C1-C8-alkyl, halo-C1-C8-alkoxy, halo-C1-C8-alkylthio, and halogen-substituted C1-C8-alkoxy-C1-C8-alkyl.
In some preferred embodiments, E3 is carbocyclyl or heterocyclyl wherein the carbocyclyl and heterocyclyl have 5 or 6 ring members and optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, keto, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the substituent is halogen, xe2x80x94OH, or keto, any substituent of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkylthio, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, and halo-C1-C6-alkylthio.
E4 is a bond, alkyl, alkenyl, xe2x80x94Oxe2x80x94, or xe2x80x94N(R3)xe2x80x94. The alkyl and alkenyl optionally are substituted.
In some preferred embodiments, E4 is a bond, xe2x80x94Oxe2x80x94, xe2x80x94N(R3)xe2x80x94, C1-C20-alkyl, or C2-C20-alkenyl. The C1-C20-alkyl and C2-C20-alkenyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen and carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, halo-C1-C8-alkyl, halo-C1-C8-alkoxy, halocarbocyclyl, halogen-substituted carbocyclyl-C1-C8-alkyl, and halogen-substituted C1-C8-alkoxy-C1-C8-alkyl.
In some preferred embodiments, E4 is a bond, xe2x80x94Oxe2x80x94, xe2x80x94N(R3)xe2x80x94, C1-C3-alkyl, or C2-C3-alkenyl. The C1-C3-alkyl and C2-C3-alkenyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen and carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, halocarbocyclyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.
In some preferred embodiments, E4 is a bond, xe2x80x94Oxe2x80x94, xe2x80x94N(R3)xe2x80x94, C1-C3-alkyl, or C2-C3-alkenyl.
In some preferred embodiments, E4 is a bond.
E5 is carbocyclyl or heterocyclyl. The carbocyclyl and heterocyclyl optionally are substituted. In some preferred embodiments, the carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R)(R7), xe2x80x94C(O)(R8), xe2x80x94Sxe2x80x94R6, xe2x80x94S(O)2xe2x80x94R6, carbocyclyl, carbocyclyl-C1-C8-alkyl, halo-C1-C8-alkyl, halo-C1-C8-alkoxy, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, halocarbocyclyl, and halogen-substituted carbocyclyl-C1-C8-alkyl. The carbocyclyl and heterocyclyl also optionally are substituted with one or more substituents independently selected from the group consisting of C2-C8-alkenyl and C2-C8-alkenyl.
In some preferred embodiments, E5 is pyridinyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R)(R7), xe2x80x94C(O)(R8), xe2x80x94Sxe2x80x94R6, xe2x80x94S(O)2xe2x80x94R6, phenyl, phenyl-C1-C6-alkyl, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, halophenyl, and halogen-substituted phenyl-C1-C6-alkyl. The pyridinyl also is optionally substituted with one or more substituents independently selected from the group consisting of C2-C6-alkenyl and C2-C6-alkynyl.
In some preferred embodiments, E5 is piperidinyl, piperazinyl, imidazolyl, furanyl, thienyl, pyrimidyl, benzodioxolyl, benzodioxanyl, benzofuryl, or benzothienyl. Such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R6)(R7), xe2x80x94C(O)(R8), xe2x80x94Sxe2x80x94R6, xe2x80x94S(O)2xe2x80x94R6, phenyl, phenyl-C1-C6-alkyl, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, halophenyl, and halogen-substituted phenyl-C1-C6-alkyl. Such substituent also optionally is substituted with one or more substituents independently selected from the group consisting of C2-C6-alkenyl and C2-C6-alkynyl.
In some preferred embodiments, E5 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R6)(R7), xe2x80x94C(O)(R8), xe2x80x94Sxe2x80x94R6, xe2x80x94S(O)2xe2x80x94R6, phenyl, phenyl-C1-C6-alkyl, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, halophenyl, and halogen-substituted phenyl-C1-C6-alkyl. The phenyl also is optionally substituted with one or more substituents independently selected from the group consisting of C2-C6-alkenyl and C2-C6-alkynyl.
In some preferred embodiments, E5 is naphthalenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R6)(R7), xe2x80x94C(O)(R8), xe2x80x94Sxe2x80x94R6, xe2x80x94S(O)2xe2x80x94R6, phenyl, phenyl-C1-C6-alkyl, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, halophenyl, and halogen-substituted phenyl-C1-C6-alkyl. The naphthalenyl also is optionally substituted with one or more substituents independently selected from the group consisting of C2-C6-alkenyl and C2-C6-alkynyl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E3, E4, or E5.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, and halo-C1-C8-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H and C1-C6-alkyl.
R3 is xe2x80x94H or alkyl. The alkyl optionally is substituted.
In some preferred embodiments, R3 is xe2x80x94H, C1-C8-alkyl, or halo-C1-C8-alkyl.
In some preferred embodiments, R3 is xe2x80x94H, C1-C6-alkyl, or halo-C1-C6-alkyl.
In some preferred embodiments, R3 is xe2x80x94H or C1-C8-alkyl.
R6 and R7 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1--C8-alkyl, heterocyclyl, heterocyclyl-C1-C8-alkyl, halo-C1-C8-alkyl, halocarbocyclyl, halogen-substituted carbocyclyl-C1-C6-alkyl, haloheterocyclyl and halogen-substituted heterocyclyl-C1-C8-alkyl.
In some preferred embodiments, R6 and R7 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R8 is xe2x80x94H, C1-C8-alkyl, xe2x80x94Oxe2x80x94R9, xe2x80x94N(R9)(R10), carbocyclyl-C1-C8-alkyl, heterocyclyl-C1-C8-alkyl, halo-C1-C8-alkyl, halogen-substituted carbocyclyl-C1-C8-alkyl, or halogen-substituted heterocyclyl-C1-C8-alkyl.
In some preferred embodiments, R8 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R9, xe2x80x94N(R9)(R10), carbocyclyl-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, halo-C1-C6-alkyl, halogen-substituted carbocyclyl-C1-C6-alkyl, or halogen-substituted heterocyclyl-C1-C6-alkyl.
In some preferred embodiments, R8 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R9, xe2x80x94N(R9)(R10), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl.
R9 and R10 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, heterocyclyl-C1-C8-alkyl, halo-C1-C8-alkyl, halocarbocyclyl, halogen-substituted carbocyclyl-C1-C8-alkyl, haloheterocyclyl, and halogen-substituted heterocyclyl-C1-C8-alkyl.
In some preferred embodiments, R9 and R10 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, heterocyclyl-C1-C6-alkyl, halo-C1-C6-alkyl, halocarbocyclyl, halogen-substituted carbocyclyl-C1-C6-alkyl, haloheterocyclyl, and halogen-substituted heterocyclyl-C1-C6-alkyl.
In some preferred embodiments, R9 and R10 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, and heterocyclyl, heterocyclyl-C1-C6-alkyl.
In some embodiments, E3 is optionally-substituted heterocyclyl.
In some preferred embodiments E3 is an optionally-substituted heterocyclyl that contains only one heteroatom ring member. Examples of often suitable heterocyclyls include furanyl, tetrahydropyranyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl, dihydrothiophenyl, tetrahydrothiophenyl, pyrrolinyl, pyrrolyl, isopyrrolyl, pyrrolidinyl, pyridinyl, piperidinyl, pyranyl, dihydropyranyl, and tetrahydropyranyl.
In some preferred embodiments, E3 is optionally-substituted pyridinyl. In some such embodiments, E5 is optionally-substituted phenyl. Such compounds include, for example: 
Such compounds also include, for example: 
In some preferred embodiments, E3 is an optionally-substituted heterocyclyl selected from the group consisting of: 
Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the substituent is halogen or xe2x80x94OH, any substituent of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkylthio, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, and halo-C1-C6-alkylthio. R14 is selected from the group consisting of halogen, xe2x80x94OH, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is halogen or xe2x80x94OH, any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkylthio, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, and halo-C1-C6-alkylthio.
In some preferred embodiments, E3 is optionally-substituted furanyl. In one such embodiment, for example, E5 is optionally-substituted phenyl. Such compounds include, for example: 
In some preferred embodiments, E3 is optionally-substituted thienyl. In some such embodiments, E5 is optionally-substituted phenyl. Such compounds include, for example: 
Such compounds also include, for example: 
In some preferred embodiments, E3 is optionally-substituted pyrrolidinyl. In some such embodiments, for example, E5 is optionally-substituted phenyl. Such compounds include, for example: 
E3 also may be, for example, an optionally-substituted heterocyclyl that contains no greater and no less than two heteroatom ring members. Suitable heterocyclyls include, for example, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, dithiolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, oxathiolyl, oxathiolanyl, oxazolyl, isoxazolyl, oxazolidinyl, isoxazolidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazinyl, and morpholinyl.
In some preferred embodiments, E3 is an optionally-substituted heterocyclyl selected from the group consisting of: 
Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the substituent is halogen or xe2x80x94OH, any substituent of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkylthio, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, and halo-C1-C6-alkylthio. Such substituents also optionally are substituted with one or more substituents independently selected from the group consisting of C2-C6-alkenyl and C2-C6-alkynyl. R14 is as defined above where E3 contains only one heteroatom in its ring.
In some particularly preferred embodiments, E3 is an optionally-substituted heterocyclyl selected from the group consisting of oxazolyl and isoxazolyl. In some such embodiment, for example, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: 
In some preferred embodiments, E3 is an optionally-substituted heteroaryl selected from the group consisting of pyrazolyl and isoimidazolyl. In some such embodiments, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: 
In some preferred embodiments, E3 is an optionally-substituted heteroaryl selected from the group consisting of thiazolyl and isothiazolyl. In one such embodiment, for example, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: 
In some preferred embodiments, E3 is an optionally-substituted heteroaryl selected from the group consisting of pyrazolidinyl and imidazolidinyl. In some such embodiments, E5 is optionally-substituted carbocyclyl. In some preferred embodiments, E5 is optionally-substituted aryl, often preferably optionally-substituted phenyl. Such compounds include, for example: 
In other preferred embodiments, E5 is optionally substituted C5-C6-cycloalkyl. Such compounds include, for example: 
In some preferred embodiments, E3 is optionally-substituted oxazolidinyl. In some such embodiments, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: 
E3 also may be, for example, an optionally-substituted heterocyclyl that contains no greater and no less than 3 heteroatom ring members. Often suitable heterocyclyls include, for example, oxadiazolyl, thiadiazolyl, and triazolyl. Here, the triazolyl optionally is substituted.
In some preferred embodiments, E3 is an optionally-substituted heteroaryl selected from the group consisting of: 
Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the substituent is halogen or xe2x80x94OH, any substituent of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkylthio, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, and halo-C1-C6-alkylthio. R14 is as defined above for heterocyclyls containing 1 or 2 heteroatom ring members.
In some preferred embodiments, E3 is oxadiazolyl.
In some such embodiments, E5 is optionally-substituted phenyl. Such compounds include, for example: 
Such compounds also include, for example: 
In other embodiments, E5 is optionally-substituted naphthalenyl. Such compounds include, for example: 
In other embodiments, E5 is optionally-substituted C5-C6-cycloalkyl. Such compounds include, for example: 
In yet other embodiments, E5 is optionally-substituted heterocyclyl. Such compounds include, for example: 
Such compounds also include, for example: 
E3 also may be, for example, an optionally-substituted heterocyclyl that contains at least 4 heteroatom ring members.
In some preferred embodiments, E3 is selected from the group consisting of: 
In some such embodiments, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: 
In other such embodiments, E5 is optionally-substituted heterocyclyl. Such compounds include, for example: 
In some embodiments, E3 is an optionally-substituted carbocyclyl. E3 may be, for example, an optionally-substituted carbocyclyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, naphthalenyl, tetrahydronaphthalenyl, indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl, fluoreneyl, decalinyl, and norpinanyl.
In some preferred embodiments, E3 is optionally-substituted phenyl. In one such embodiment, for example, E5 is optionally-substituted heterocyclyl.
In some such embodiments, E5 is optionally-substituted heterocycloalkyl. Examples of such compounds include, for example: 
In other preferred embodiments, E5 is optionally-substituted, 5-member heteroaryl. Examples of such compounds include, for example: 
Such compounds also include, for example: 
In other preferred embodiments, E5 is optionally-substituted, 6-member heteroaryl.
In other preferred embodiments, E5 is optionally-substituted pyridinyl. Such compounds include, for example: 
Such compounds also include, for example: 
In other preferred embodiments, E5 is optionally-substituted pyrimidinyl. Such compounds include, for example: 
In other preferred embodiments, E5 is optionally-substituted, multi-ring heterocyclyl. Such compounds include, for example: 
In some preferred embodiments, for example, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl,
In some preferred embodiments, E5 is optionally-substituted phenyl. Such compounds include, for example: 
Other such compounds include, for example: 
In other preferred embodiments, E5 is optionally-substituted naphthalenyl. Such compounds include, for example: 
In some embodiments of this invention, the compound has a structure to Formula IV: 
A1, A2, and A3 are as defined above for Formula I.
E1 is s xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 is alkyl, cycloalkyl, alkylcycloaklyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
In some preferred embodiments, E2 is C1-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, and halo-C1-C6alkyl.
In some preferred embodiments, E2 is C1-C6-alkyl, cycloalkyl, C1-C6alkylcycloalkyl, cycloalkyl-C1-C6-alkyl, or C1-C6-alkylcycloalkyl-C1-C6-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C2-alkyl, and halo-C1-C2-alkyl.
In some preferred embodiments, E2 is C1-C6-alkyl, cycloalkyl, C1-C6-alkylcycloalkyl, cycloalkyl-C1-C6-alkyl, or C1-C6-alkylcycloalkyl-C1-C6-alkyl. Any member of this group optionally is substituted with one or more C1-C2-alkyl.
E4 is a bond or alkyl. The alkyl optionally is substituted.
In some preferred embodiments, E4 is a bond, C1-C20-alkyl, or halo-C1-C20-alkyl.
In some preferred embodiments, E4 is a bond, C1-C3-alkyl, or halo-C1-C3-alkyl.
In some preferred embodiments, E4 is a bond or C1-C3-alkyl.
In some preferred embodiments, E4 is a bond.
E5 is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
In some preferred embodiments, E5 is C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, or heterocyclyl. The C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halo-C1-C8-alkoxy, xe2x80x94N(R7)(R8), xe2x80x94C(O)(R9), xe2x80x94Sxe2x80x94R7, xe2x80x94S(O)2xe2x80x94R7, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C8-alkyl, and halogen-substituted C1-C8-alkoxy-C1-C8alkyl.
In some preferred embodiments, E5 is C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, carbocyclyl, or heterocyclyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkoxy, xe2x80x94N(R7)(R8), xe2x80x94C(O)(R9), xe2x80x94Sxe2x80x94R7, xe2x80x94S(O)2xe2x80x94R7, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituented C1-C6-alkoxy-C1-C6-alkyl.
E6 is xe2x80x94H, halogen, or alkyl. The alkyl optionally is substituted.
In some preferred embodiments, E6 is xe2x80x94H, halogen, or C1-C8-alkyl. The C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, E6 is xe2x80x94H, halogen, or C1-C6-alkyl. The C1-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
E7 is xe2x80x94H, alkyl, alkenyl, alkynyl, xe2x80x94S(O)2xe2x80x94R3, xe2x80x94NO2, xe2x80x94C(O)xe2x80x94N(R3)(R4), xe2x80x94(C)(OR3), carbocyclyl, carbocyclylalkyl, alkoxycarbocyclyl, xe2x80x94CN, xe2x80x94Cxe2x95x90Nxe2x80x94OH, or xe2x80x94Cxe2x95x90NH. The alkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, and alkoxycarbocyclyl optionally are substituted.
In some preferred embodiments, E7 is xe2x80x94H, C1-C8-alkyl, C1-C8-alkenyl, C1-C8-alkynyl, xe2x80x94S(O)2xe2x80x94R3, xe2x80x94NO2, xe2x80x94C(O)xe2x80x94N(R3)(R4), xe2x80x94(C)(OR3), carbocyclyl, carbocyclyl-C1-C8-alkyl, C1-C8-alkoxycarbocyclyl, xe2x80x94CN, xe2x80x94Cxe2x95x90Nxe2x80x94OH, or xe2x80x94Cxe2x95x90NH. The C1-C6-alkyl, C1-C6-alkenyl, C1-C8-alkynyl, carbocyclyl, carbocycyl-C1-C8-alkyl, or C1-C8-alkoxycarbocyclyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, E7 is xe2x80x94H, C1-C6-alkyl, C1-C6-alkenyl, C1-C6-alkynyl, xe2x80x94S(O)2xe2x80x94R3, xe2x80x94NO2, xe2x80x94C(O)xe2x80x94N(R3)(R4), xe2x80x94(C)(OR3), carbocyclyl, carbocycly-C1-C6-alkyl, C1-C6-alkoxycarbocycyly, xe2x80x94CN, xe2x80x94Cxe2x95x90Nxe2x80x94OH, or xe2x80x94Cxe2x95x90NH. The C1-C6-alkyl, C1-C6-alkenyl, C1-C6-alkynyl, carbocyclyl, carbocycyl-C1-C6-alkyl, or C1-C6-alkoxycarbocyclyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E4, E5, E6, or E7.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, and halo-C1-C8-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H and C1-C6-alkyl.
R3 and R4 are independently selected from the group consisting of xe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted.
In some preferred embodiments, R3 and R4 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R3 and R4 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R7 and R8 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R7 and R8 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R9 is xe2x80x94H, C1-C8-alkyl, xe2x80x94Oxe2x80x94R10, xe2x80x94N(R10)(R11), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R9 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R10, xe2x80x94N(R10)(R11), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R10 and R11 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R10 and R11 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferred not substituted with halogen.
In some preferred embodiments, E5 is optionally-substituted carbocyclyl or optionally-substituted heterocyclyl. For example, in some such embodiments, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferred optionally-substituted phenyl. Such compounds include, for example: 
In some preferred embodiments E5 is C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, or C1-C6-alkoxy-C1-C6-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN.
In some preferred embodiments, E5 is optionally-substituted C1-C6-alkyl, with the C1-C6-alkyl often being more preferably unsubstituted. Such compounds include, for example: 
In some embodiments of this invention, the compound has a structure corresponding to Formula V: 
A1, A2, and A3 are as defined above for Formula I.
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R3)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R3)xe2x80x94, xe2x80x94N(R3)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 is a bond, alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Except where the member is a bond, any member of such group optionally is substituted.
In some preferred embodiments, E2 is a bond, C-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group (except for the bond) optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, E2 is a bond, C1-C6-alkyl, or halo-C1-C6-alkyl.
In some preferred embodiments E2 is a bond or C1-C6-alkyl.
E3 is carbonylpyrrollidinyl. The carbonylpyrrollidinyl optionally is substituted.
In some preferred embodiments, E3 is carbonylpyrrollidinyl wherein the carbonylpyrrollidinyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.
In some preferred embodiments, E4 is a bond, C1-C20-alkyl, halo-C1-C20-alkyl, C2-C20-alkenyl, or halo-C2-C20-alkenyl.
In some preferred embodiments, E4 is a bond, C1-C3-alkyl, halo-C1-C3-alkyl, C2-C3-alkenyl, or balo-C2-C3-alkenyl.
In some preferred embodiments, E4 is a bond, C1-C3-alkyl, or C2-C3-alkenyl.
In some preferred embodiments, E4 is a bond.
E5 is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
In some preferred embodiments, E5 is C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, or heterocyclyl. The C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C6-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C8-alkyl, and halogen-substituted carbocyclyl-C1-C8-alkyl.
In some preferred embodiments, E5 is C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, carbocyclyl, or heterocyclyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.
R1 and R2 are independently selected from group xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E3, E4, or E5.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H and C1-C6-alkyl.
R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R7 is xe2x80x94H, C1-C8-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R7 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, the compound has a structure corresponding to Formula V-A: 
In some preferred embodiments, E5 is optionally-substituted carbocyclyl or optionally substituted heterocyclyl. For example, in some such embodiments, E5 is optionally substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: 
In some preferred embodiments, E5 is optionally-substituted C5-C6-cycloalkyl. Such compounds include, for example: 
In some preferred embodiments, E5 is C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, or C1-C8-alkoxy-C1-C8-alkyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN.
In some preferred embodiments, E5 is optionally-substituted C1-C8-alkyl, with C1-C8-alkyl often being more preferred. Such compounds include, for example: 
In some embodiments of this invention, the compound has a structure corresponding to Formula VI: 
A1, A2, and A3 are as defined above for Formula I.
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, and haloalkyl.
In some preferred embodiments, E2 is C1-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, E2 is C1-C6-alkyl, cycloalkyl, C1-C6-alkylcycloalkyl, cycloalkyl-C1-C6-alkyl, or C1-C6-alkylcycloalkyl-C1-C6-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C2-alkyl, and halo-C1-C2-alkyl.
In some preferred embodiments, E2 is C1-C6-alkyl, cycloalkyl, C1-C6-alkylcycloalkyl, cycloalkyl-C1-C6-alkyl, or C1-C6-alkylcycloalkyl-C1-C6-alkyl. Any member of this group optionally is substituted with one or more C1-C2-alkyl.
E5 is alkyl, alkenyl, alkynyl, cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, or cyclohexadienyl. Here, the cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl optionally are substituted. The alkyl, alkenyl, and alkynyl (a) contain at least 4 carbon atoms, and (b) optionally are substituted with one or more substituents selected from the group consisting of xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, and halogen.
In some preferred embodiments, E5 is C4-C20-alkyl, C4-C20-alkenyl, C4-C20-alkynyl, cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, or cyclohexadienyl. The C4-C20-alkyl, C4-C20-alkenyl, and C4-C20-alkynyl optionally are substituted with one or more substituents independently selected from the group consisting of xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, and halogen. The cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C8-alkyl, and halogen-substituted carbocyclyl-C1-C8-alkyl.
In some preferred embodiments, E5 is C4-C8-alkyl, C4-C8-alkenyl, C4-C8-alkynyl, cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, or cyclohexadienyl. The C4-C8-alkyl, C4-C8-alkenyl, and C4-C8-alkynyl optionally are substituted with one or more substituents independently selected from the group consisting of xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, and halogen. The cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substitute carbocyclyl-C1-C6-alkyl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E5.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, and halo-C1-C8-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H and C1-C6-alkyl.
R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R7 is xe2x80x94H, C1-C8-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R7 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, E5 is C4-C8-alkyl, C4-C8-alkenyl, or C4-C8-alkynyl. The C4-C8-alkyl, C4-C8-alkenyl, and C4-C8-alkynyl optionally are substituted with one or more substituents independently selected from the group consisting of xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, and halogen. Such compounds include, for example: 
In some preferred embodiments, E5 is optionally-substituted carbocyclyl. In some such embodiments, E5 is optionally-substituted C5-C6-cycloalkyl. Such compounds include, for example: 
In other embodiments, E5 is an optionally-substituted, partially-saturated carbocyclyl selected from the group consisting of cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl. Such compounds include, for example: 
In some embodiments of this invention, the compound has a structure to Formula VII: 
A1, A2, and A3 are as defined above for Formula I.
E2 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkyl. Any member of this group optionally is substituted.
In some preferred embodiments, E2 is C1-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, E2 is C1-C6-alkyl optionally substituted with one or more halogen.
In some preferred embodiments, E2 is C1-C6-alkyl.
E3 is carbonylpiperidinyl. The carbonylpiperidinyl optionally is substituted.
In some preferred embodiments, E3 is carbonylpiperidinyl wherein the carbonylpiperidinyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, the compound has a structure corresponding to one of the following formulas: 
E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.
In some preferred embodiments, E4 is a bond, C1-C20-alkyl, halo-C1-C20alkyl, C2-C20-alkenyl, or halo-C2-C20-alkenyl.
In some preferred embodiments, E4 is a bond, C1-C3-alkyl, halo-C1-C3-alkyl, C2-C3-alkenyl, or halo-C2-C3-alkenyl.
In some preferred embodiments, E4 is a bond, C1-C3-alkyl, or C2-C3-alkenyl.
In some preferred embodiments, E4 is a bond.
E5 is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
In some preferred embodiments, E5 is C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, or heterocyclyl. The C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, and carbocyclyl-C1-C8-alkyl.
In some preferred embodiments, E5 is C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, carbocyclyl, or heterocyclyl. Here, the C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and C1-C6-alkoxy-C1-C6-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H, and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E3, E4, or E5.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H and C1-C6-alkyl.
R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R7 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R7 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, E5 is optionally-substituted carbocyclyl or optionally substituted heterocyclyl. In some such embodiments, E5 is optionally-substituted aryl, often preferably optionally-substituted phenyl. Such compounds include, for example: 
In some embodiments of this invention, the compound has a structure corresponding to Formula VIII: 
A1, A2, and A3 are as defined above for Formula I.
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 forms a link of at least 3 carbon atoms between E1 and E5. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
In some preferred embodiments, E2 is C3-C20-alkyl, cycloalkyl, C1-C10-alkyl-cycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkyl-cycloalkyl-C1-C10-alkyl. Any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, E2 is C3-C6-alkyl optionally substituted with one or more halogen.
In some preferred embodiments, E2 is C3-C6-alkyl.
E5 is optionally-substituted heterocyclyl, optionally-substituted fused-ring carbocyclyl, or substituted single-ring carbocyclyl.
In some preferred embodiments, E5 is single-ring carbocyclyl, fused-ring carbocyclyl, or heterocyclyl.
Here, the single-ring carbocyclyl is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C8-alkyl, halogen-substituted carbocyclyl-C1-C8-alkyl. The single-ring carbocyclyl also optionally is substituted on the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming C5-C6-cycloalkyl or halo-C5-C6-cycloalkyl.
In some preferred embodiments, the single-ring carbocyclyl is substituted with one or more substituents independently selected from the group consisting of and halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94S-R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl. The single-ring carbocyclyl also optionally is substituted on the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming C5-C6-cycloalkyl or halo-C5-C6-cycloalkyl.
The heterocyclyl and fused-ring carbocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of and halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, and carbocyclyl-C1-C6-alkyl. The heterocyclyl and fused-ring carbocyclyl also optionally are substituted on the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming C5-C6-cycloalkyl or halo-C5-C6-cycloalkyl.
In some preferred embodiments, the heterocyclyl and fused-ring carbocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of and halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl. The heterocyclyl and fused-ring carbocyclyl also optionally are substituted the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming C5-C6-cycloalkyl or halo-C5-C6cycloalkyl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E5.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, and halo-C1-C8-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H and C1-C6-alkyl.
R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R7is xe2x80x94H, C1-C8-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R7 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, E5 is a substituted single-ring carbocyclyl. E5 may be, for example a substituted single-ring carbocyclyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl.
In some preferred embodiments, E5 is substituted phenyl. Such compounds include, for example: 
Such compounds also include, for example: 
In some preferred embodiments, E5 is optionally-substituted fused-ring carbocyclyl. E5 may be, for example, optionally-substituted fused-ring carbocyclyl selected from the group consisting of naphthalenyl, tetrahydronaphthalenyl, indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl, fluroreneyl, decalinyl, and norpinanyl.
In some preferred embodiments, E5 is optionally-substituted naphthalenyl. Such compounds include, for example: 
In some preferred embodiments, E5 is optionally-substituted, single-ring heterocyclyl.
In some preferred embodiments, E5 is an optionally-substituted pyridinyl. Such compounds include, for example: 
In some preferred embodiments, E5 is an optionally-substituted heterocyclyl selected from the group consisting of imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, and pyrazolidinyl. Such compounds include, for example: 
In some preferred embodiments, E5 is optionally-substituted fused-ring heterocyclyl. E5 may be, for example, an optionally-substituted fused-ring heterocyclyl selected from the group consisting of indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofiranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, tetrahydroisoquinolinyl, carbazolyl, xanthenyl, and acridinyl. Compounds wherein E5 is an optionally-substituted fused-ring heterocyclyl include, for example: 
In some preferred embodiments, E5 is optionally-substituted tetrahydroisoquinolinyl. Such compounds include, for example: 
In some preferred embodiments, E5 is heterocyclyl that is substituted on the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming C5-C6-cycloalkyl or halo-C5-C6-cycloalkyl. This heterocyclyl also optionally is substituted with one or more substituents independently selected from the group consisting of and halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocycly-C1-C6-alkyl. The heterocyclyl that is substituted may be, for example, selected from the group consisting of dihydrofuranyl, tetrahydrofuranyl dihydrothiophenyl, tetrahydrothiophenyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, dithiolyl, oxathiolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, oxathiolanyl, pyranyl, dihydropyranyl, piperidinyl, piperazinyl, and morpholinyl. Such compounds include, for example: 
In some embodiments of this invention, the compound has a structure corresponding to Formula IX: 
A1, A2, and A3 are as defined above for Formula I.
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 forms a link of at least 4 carbon atoms between E1 and E5. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
In some preferred embodiments, E2 is C4-C20-alkyl, cycloalkyl, C1-C10-alkyl-cycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkyl-cycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, E2 is C4-C6-alkyl optionally substituted with one or more halogen.
In some preferred embodiments, E2 is C4-C6-alkyl.
E5 is xe2x80x94OH or optionally-substituted carbocyclyl.
In some preferred embodiments, E5 is xe2x80x94OH or carbocyclyl wherein the carbocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of and halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C8-alkyl, halo-C1-C-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C8-alkyl. The carbocyclyl also optionally is substituted with two C1-C8-alkyl or halo-C1-C8-alkyl groups on the same atom that form a C5-C6-cycloalkyl or C5-C6-halocycloalkyl.
In some preferred embodiments, E5 is xe2x80x94OH or carbocyclyl wherein the carbocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of and halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E5.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, and halo-C1-C8-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H and C1-C6-alkyl.
R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R7 is xe2x80x94H, C1-C8-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R7 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen. Such compounds include, for example:
In some preferred embodiments, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: 
In some preferred embodiments, E5 is xe2x80x94OH. Such compounds include, for example: 
In some embodiments of this invention, the compound has a structure corresponding to Formula X: 
A1, A2, and A3 are as defined above for Formula I.
E1 is xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
In some preferred embodiments, E2 is C1-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, C1-C6-alkyl.
In some preferred embodiments, E2 is C2-C6-alkyl optionally substituted with one or more halogen.
In some preferred embodiments, E2 is C2-C6-alkyl.
E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.
In some preferred embodiments, E4 is a bond, C1-C20-alkyl, halo-C1C20-alkyl, C2-C20-alkenyl, or halo-C2-C20-alkenyl.
In some preferred embodiments E4 is a bond, C1-C3-alkyl, halo-C1-C3-alkyl, C2-C3-alkenyl, or halo-C2-C3-alkenyl.
In some preferred embodiments, E4 is a bond, C1-C3-alkyl, or C2-C3-alkenyl.
E5 is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
In some preferred embodiments, E5 is C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, or heterocyclyl. The C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C8-alkyl, and halogen-substituted carbocyclyl-C1-C8-alkyl.
In some preferred embodiments, E5 is C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, carbocyclyl, or heterocyclyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E4, or E5.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, and halo-C1-C8-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H and C1-C6-alkyl.
R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R7 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R7 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, E5 is C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-8-alkoxy, or C1-C8-alkoxy-C1-C8-alkyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN.
In some preferred embodiments, E5 is C1-C8-alkyl. Such compounds include, for example: 
In some embodiments of this invention, the compound has a structure to Formula XI: 
A1, A2, and A3 are as defined above for Formula I.
E2 comprises at least 3 carbon atoms. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally substituted.
In some preferred embodiments, E2 is C3-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, E2 is C3-C10-alkyl optionally is substituted with one or more halogen.
In some preferred embodiments, E2 is C3-C10-alkyl.
In some preferred embodiments, E2 is C3-C5-alkyl.
E5 is xe2x80x94H, alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, carbocyclylalkoxyalkyl, heterocyclyl, heterocyclylalkyl, or heterocyclylalkoxyalkyl. The alkyl, alkenyl, alkynyl, and alkoxyalkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl, carbocyclylalkoxyalkyl, heterocyclyl, heterocyclylalkyl, and heterocyclylalkoxyalkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, halogen-substituted alkoxyalkyl, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclyalkyl.
In some preferred embodiments, E5 is xe2x80x94H, C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, carbocyclyl-C1-C10-alkoxy-C1-C10-alkyl, heterocyclyl, heterocyclyl-C1-C10-alkyl, or heterocyclyl-C1-C10-alkoxy-C1-C10alkyl. The C2-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl, carbocyclyl-C1-C10-alkoxy-C1-C10-alkyl, heterocyclyl, heterocyclyl-C1-C10-alkyl, and heterocyclyl-C1-C10-alkoxy-C1-C10-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C8-alkyl, and halogen-substituted carbocyclyl-C1-C8-alkyl.
In some preferred embodiments, E5 is xe2x80x94H, C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy-C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkoxy-C1-C8-alkyl, heterocyclyl, heterocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkoxy-C1-C8-alkyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl, carbocyclyl-C1-C8-alkoxy-C1-C8-alkyl, heterocyclyl, heterocyclyl-C1-C8-alkyl, and heterocyclyl-C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R3 is xe2x80x94H, alkyl, xe2x80x94Oxe2x80x94R4, xe2x80x94N(R4)(R5), carbocyclylalkyl, or heterocyclylalkyl. The alkyl, carbocyclylalkyl, or heterocyclylalkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R3 is xe2x80x94H, C1-C8-alkyl, xe2x80x94Oxe2x80x94R4, xe2x80x94N(R4)(R5), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R3 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R4, xe2x80x94N(R4)(R5), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R4 and R5 are independently selected from the group consisting of xe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R4 and R5 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R4 and R5 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, E5 is xe2x80x94H, C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, or C1-C8-alkoxy-C1-C8-alkyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. Such compounds include, for example: 
In some preferred embodiments, E5 is carbocyclyl, carbocyclyl-C1-C8-alkoxy-C1-C8-alkyl, heterocyclyl, heterocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkoxy-C1-C8-alkyl, the carbocyclyl, carbocyclyl-C1-C8-alkoxy-C1-C8-alkyl, heterocyclyl, heterocyclyl-C1-C8-alkyl, and heterocyclyl-C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.
In some preferred embodiments, E5 is optionally-substituted carbocyclyl.
In some preferred embodiments, E5 is optionally-substituted phenyl. Such compounds include, for example: 
In some preferred embodiments, E5 is optionally-substituted naphthalenyl. Such compounds include, for example: 
In some preferred embodiments, E5 is heterocyclyl or heterocyclyl-C1-C8-alkyl. Such compounds include, for example: 
In some embodiments of this invention, the compound has a structure to Formula XII: 
A1, A2, and A3 are as defined above for Formula I.
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkyl. Any member of this group optionally is substituted. An atom in E2 optionally is bound to an atom in E5 to form a ring.
In some preferred embodiments, E2 is C1-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more substituents selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl.
In some preferred embodiments, E2 is C2-C6-alkyl optionally substituted with one or more halogen.
In some preferred embodiments, E2 is C2-C6-alkyl.
E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.
In some preferred embodiments, E4 is a bond, C1-C20-alkyl, halo-C1-C20-alkyl, C2-C20-alkenyl, or halo-C2-C20-alkenyl.
In some preferred embodiments, E4 is a bond, C1-C3-alkyl, halo-C1-C3-alkyl, C2-C3-alkenyl, or halo-C2-C3-alkenyl.
In some preferred embodiments, E4 is a bond, C1-C3-alkyl, or C2-C3-alkenyl.
In some preferred embodiments, E4 is methyl.
In some preferred embodiments, E4 is a bond.
E5 is:
an optionally-substituted radical selected from the group consisting of alkenyl, alkynyl, alkoxy, alkoxyalkyl, fused-ring carbocyclyl, and heterocyclyl; or
single-ring carbocyclyl substituted with one or more substituents independently selected from the group consisting of xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, halogen-substituted carbocyclylalkyl, heterocyclyl, haloheterocyclyl, heterocyclylalkyl, and halogen-substituted heterocyclylalkyl; or
single-ring carbocyclyl having multiple substitutions.
In some preferred embodiments, E5 is C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, C1-C20-alkoxy-C1-C20-alkyl, heterocyclyl, single-ring carbocyclyl, or fused-ring carbocyclyl. The C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The heterocyclyl and fused-ring carbocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, halogen-substituted carbocyclyl-C1-C8-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-C1-C8-alkyl, and halogen-substituted heterocyclyl-C1-C8-alkyl. The single-ring carbocyclyl is either:
substituted with one or more substituents independently selected from the group consisting of xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C8-alkyl, halogen-substituted carbocyclyl-C1-C8-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-C1-C8-alkyl, and halogen-substituted heterocyclyl-C1-C8-alkyl, or
substituted with 2 or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C8-alkyl, halogen-substituted carbocyclyl-C1-C8-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-C1-C8-alkyl, and halogen-substituted heterocyclyl-C1-C8-alkyl.
In some preferred embodiments, E5 is C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, C1-C8-alkoxy-C2-C8-alkyl, heterocyclyl, single-ring carbocyclyl, or fused-ring carbocyclyl. The C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The heterocyclyl and fused-ring carbocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, halogen-substituted carbocyclyl-C1-C6-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-C1-C6-alkyl, and halogen-substituted heterocyclyl-C1-C6-alkyl. The single-ring carbocyclyl is either:
substituted with one or more substituents independently selected from the group consisting of xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, halogen-substituted carbocyclyl-C1-C6-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-C1-C6alkyl, and halogen-substituted heterocyclyl-C1-C6-alkyl; or
substituted with 2 or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, halogen-substituted carbocyclyl-C1-C6-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-C1-C6-alkyl, and halogen-substituted heterocyclyl-C1-C6-alkyl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R3 is xe2x80x94H, alkyl, xe2x80x94Oxe2x80x94R4, xe2x80x94N(R4)(R5), carbocyclylalkyl, or heterocyclylalkyl. The alkyl, carbocyclylalkyl, or heterocyclylalkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R3 is xe2x80x94H, C1-C8-alkyl, xe2x80x94Oxe2x80x94R4, xe2x80x94N(R4)(R5), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R3 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R4, xe2x80x94N(R4)(R5), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with hyalogen.
In some preferred embodiments, R3 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R4, xe2x80x94N(R4)(R5), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R4 and R5 are independently selected from the group consisting of xe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R4 and R5 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R4 and R5 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, E2 is bound to an atom of E5 to form a ring. Such compounds include, for example: 
In some preferred embodiments, E2 is not bound to an atom of E5 to form a ring.
In some such preferred embodiments, E5 is a single-ring carbocyclyl (preferably phenyl) substituted with one or more substituents independently selected from the group consisting of xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocycyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, halogen-substituted carbocyclyl-C1-C6-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-C1-C6-alkyl, and halogen-substituted heterocyclyl-C1-C6-alkyl. Such compounds include, for example: 
In some preferred embodiments, E5 is single-ring carbocyclyl (preferably phenyl) substituted with 2 or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-C1-C6-alkyl, and halogen-substituted heterocyclyl-C1-C6-alkyl. Such compounds include, for example: 
In some preferred embodiments, E5 is heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, halogen-substituted carbocyclyl-C1-C6-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-C1-C6-alkyl, and halogen-substituted heterocyclyl-C1-C6-alkyl. Such compounds include, for example: 
In some embodiments of this invention, the compound has a structure corresponding to Formula XIII: 
A1, A2, and A3 are as defined above for Formula I.
E1 is xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
In some preferred embodiments, E2 is C1-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more substituents selected from the group consisting of halogen, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, E2 is C1-C6-alkyl, cycloalkyl, C1-C6-alkylcycloalkyl, cycloalkyl-C1-C6-alkyl, or C1-C6-alkylcycloalkyl-C1-C6-alkyl. Any member of this group optionally is substituted with one or more halogen, although such substituent typically is preferably not substituted with halogen.
E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.
In some preferred embodiments, E4 is a bond, C1-C20-alkyl, halo-C1-C20-alkyl, C2-C20-alkenyl, or halo-C2-C20-alkenyl.
In some preferred embodiments, E4 is a bond, C1-C3-alkyl, halo-C1-C3-alkyl, C2-C3-alkenyl, or halo-C2-C3-alkenyl.
In some preferred embodiments, E4 is a bond, C1-C3-alkyl, or C2-C3-alkenyl.
E5 is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
In some preferred embodiments, E5 is C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, or heterocyclyl. The C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, xe2x80x94N5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C8-alkyl, and halogen-substituted carbocyclyl-C1-C8-alkyl.
In some preferred embodiments, E5 is C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, carbocyclyl, or heterocyclyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E4, or E5.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, and halo-C1-C8-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H and C1-C6-alkyl.
R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R7 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R7 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some embodiments of this invention, the compound has a structure corresponding to Formula XIV: 
A1, A2, and A3 are as defined above for Formula I.
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
In some preferred embodiments, E2 is C1-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl; or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, E2 is C1-C6-alkyl optionally substituted with one or more halogen.
In some preferred embodiments, E2 is C1-C6-alkyl.
E4 is alkyl or alkenyl. The alkyl and alkenyl optionally are substituted.
In some preferred embodiments, E4 is C1-C20-alkyl, halo-C1-C20-alkyl, C2-C20-alkenyl, or halo-C2-C20-alkenyl.
In some preferred embodiments, E4 is C1-C3-alkyl, halo-C1-C3-alkyl, C2-C3-alkenyl, or halo-C2-C3-alkenyl.
In some preferred embodiments, E4 is C1-C3-alkyl or C2-C3-alkenyl.
E5 is xe2x80x94H, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
In some preferred embodiments, E5 is xe2x80x94H, C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, carbocyclyl, or heterocyclyl. The C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, and C1-C20-alkoxy optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C8-alkyl, and halogen-substituted carbocyclyl-C1-C8-alkyl.
In some preferred embodiments, E5 is xe2x80x94H, C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, carbocyclyl, or heterocyclyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, and C1-C8-alkoxy optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.
R3 and R4 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R3 and R4 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R5 is xe2x80x94H, C1-C8-alkyl, xe2x80x94Oxe2x80x94R6, xe2x80x94N(R6)(R7), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R5 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R6, xe2x80x94N(R6)(R7), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R6 and R7 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R6 and R7 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, E5 is xe2x80x94H, C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, or C1-C8-alkoxy. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, and C1-C8-alkoxy optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. In one such embodiment, E5 is C1-C8-alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. Such compounds include, for example: 
In some preferred embodiments, E5 is optionally-substituted carbocyclyl and optionally-substituted heterocyclyl.
In some preferred embodiments, E5 is optionally-substituted aryl, often preferably optionally-substituted phenyl. Such compounds include, for example: 
In some embodiments of this invention, the compound has a structure corresponding to Formula XV: 
A1, A2, and A3 are as defined above for Formula I.
E2 comprises less than 5 carbon atoms. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted, but preferably is not substituted.
E5 is alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
In some preferred embodiments, E5 is C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, or heterocyclyl. The C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C8-alkyl, halogen-substituted carbocyclyl-C1-C8-alkyl, C1-C8-alkylcarbocyclyloxy, and halogen-substituted C1-C8-alkylcarbocyclyloxy.
In some preferred embodiments, E5 is C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy-C1-C8-alkyl, carbocyclyl, or heterocyclyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, halogen-substituted carbocyclyl-C1-C6-alkyl, C1-C6-alkylcarbocyclyloxy, and halogen-substituted C1-C6-alkylcarbocyclyloxy.
R3 and R4 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R3 and R4 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R5 is xe2x80x94H, C1-C8-alkyl, xe2x80x94Oxe2x80x94R6, xe2x80x94N(R6)(R7), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R5 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R6, xe2x80x94N(R6)(R7), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R6 and R7 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R6 and R7 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, E5 is C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, or C1-C8-alkoxy-C1-C8-alkyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN.
In some preferred embodiments, E5 is optionally-substituted carbocyclyl.
In some preferred embodiments, E5 is optionally-substituted C5-C6-cycloalkyl. Such compounds include, for example: 
In some preferred embodiments, E5 is optionally-substituted phenyl. Such compounds include, for example: 
In some preferred embodiments, E5 is optionally-substituted heterocyclyl.
In some preferred embodiments, E5 is optionally-substituted heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, and tetrahydroisoquinolinyl. Such compounds include, for example: 
In some embodiments of this invention, the compound has a structure corresponding to Formula XVI: 
A1, A2, and A3 are as defined above for Formula I.
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
In some preferred embodiments, E2 is C1-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, halo-C1-C6-alkyl.
In some preferred embodiments, E2 is C1-C6-alkyl optionally substituted with one or more halogen.
In some preferred embodiments, E2 is C1-C6-alkyl.
E5 is alkyl, alkenyl, alkynyl, alkoxyalkyl, saturated carbocyclyl, partially saturated carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
In some preferred embodiments, E5 is C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy-C1-C20-alkyl, saturated carbocyclyl, partially saturated carbocyclyl, or heterocyclyl. The C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The saturated carbocyclyl, partially saturated carbocyclyl, and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, halogen-substituted carbocyclyl-C1-C8-alkyl, C1-C8-alkylcarbocyclyloxy, and halogen-substituted C1-C8-alkylcarbocyclyloxy.
In some preferred embodiments, E5 is C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy-C1-C8-alkyl, saturated carbocyclyl, partially saturated carbocyclyl, or heterocyclyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The saturated carbocyclyl, partially saturated carbocyclyl, and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, halogen-substituted carbocyclyl-C1-C6-alkyl, C1-C6-alkylcarbocyclyloxy, and halogen-substituted C1-C6-alkylcarbocyclyloxy.
R3 and R4 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R3 and R4 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R5 is s xe2x80x94H, C1-C8-alkyl, xe2x80x94Oxe2x80x94R6, xe2x80x94N(R6)(R7), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R5 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R6, xe2x80x94N(R6)(R7), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R6 and R7 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R6 and R7 are independently selected from the group consisting of xe2x80x94H, C1‥C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, E5 is C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, or C1-C8-alkoxy-C1-C8-alkyl. The C-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN.
In some preferred embodiments, E5 is optionally-substituted, partially-saturated carbocyclyl.
In some preferred embodiments, E5 is optionally-substituted, saturated carbocyclyl (preferably optionally-substituted C5-C6 cycloalkyl). Such compounds include, for example: 
In some preferred embodiments, E5 is optionally-substituted heterocyclyl. Such compounds include, for example: 
In some embodiments of this invention, the compound has a structure corresponding to Formula XVII: 
A1, A2, and A3 are as defined above for Formula I.
E1 is xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 is alkyl, carbocyclyl, alkylcycloalkyl, cycloalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
In some preferred embodiments, E2 is C1-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, E2 is C1-C6-alkyl optionally substituted with one or more halogen.
In some preferred embodiments, E2 is C1-C6-alkyl.
E4 is a bond, alkyl, or alkenyl, The alkyl and alkenyl optionally are substituted.
In some preferred embodiments, E4 is a bond, C1-C20-alkyl, halo-C1-C20-alkyl, C2-C20-alkenyl, or halo-C2-C20-alkenyl.
In some preferred embodiments, E4 is a bond, C1-C3-alkyl, halo-C1-C3-alkyl, C2-C3-alkenyl, or halo-C2-C3-alkenyl.
In some preferred embodiments, E4 is a bond, C1-C3-alkyl, or C2-C3-alkenyl.
E5 is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.
In some preferred embodiments, E5 is C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, or heterocyclyl. The C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, balocarbocyclyl, carbocyclyl-C1-C8-alkyl, and halogen-substituted carbocyclyl-C1-C8-alkyl.
In some preferred embodiments, E5 is C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, carbocyclyl, or heterocyclyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, and xe2x80x94CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E4, or E5.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, and halo-C1-C8-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H and C1-C6-alkyl.
R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R7 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R7 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some embodiments of this invention, the compound has a structure corresponding to Formula XVII: 
A1, A2, and A3 are as defined above for Formula I.
E2 is a bond, alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
In some preferred embodiments, E2 is a bond, C1-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, E2 is a bond, C1-C6-alkyl, or halo-C1-C6-alkyl.
In some preferred embodiments, E2 is a bond or C1-C6-alkyl.
In some preferred embodiments, E2 is a bond.
E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.
In some preferred embodiments, E4 is a bond, C1-C20-alkyl, halo-C1-C20-alkyl, C2-C20-alkenyl, or halo-C2-C20-alkenyl.
In some preferred embodiments, E4 is a bond, C1-C3-alkyl, halo-C1-C3-alkyl, C2-C3-alkenyl, or halo-C2-C3-alkenyl.
In some preferred embodiments, E4 is a bond, C1-C3-alkyl, or C2-C3-alkenyl.
In some preferred embodiments, E4 is a bond.
E5 is optionally-substituted heterocyclyl or substituted carbocyclyl.
The E5 heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, halogen-substituted alkoxyalkyl, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl.
In some preferred embodiments, E5 is heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C8-alkoxy-C1-C6-alkyl, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C8-alkyl.
In some preferred embodiments, E5 is heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.
The E5 carbocyclyl is substituted with:
2 or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, halogen-substituted alkoxyalkyl, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl; or
a substituent selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)xe2x80x94Oxe2x80x94R3, xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl.
In some preferred embodiments, E5 is carbocyclyl substituted with:
2 or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C8-alkyl, and halogen-substituted carbocyclyl-C1-C8-alkyl, or
a substituent selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)xe2x80x94Oxe2x80x94R3, xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C8-alkyl, and halogen-substituted carbocyclyl-C1-C8alkyl.
In some preferred embodiments, E5 is carbocyclyl substituted with:
2 or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R3)(R4), xe2x80x94C(O)(R5), xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl, or
a substituent selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)xe2x80x94Oxe2x80x94R3, xe2x80x94Sxe2x80x94R3, xe2x80x94S(O)2xe2x80x94R3, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.
R3 and R4 are independently selected from the group consisting of xe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R3 and R4 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R3 and R4 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R5 is xe2x80x94H, alkyl, xe2x80x94Oxe2x80x94R6, xe2x80x94N(R6)(R7), carbocyclylalkyl, or heterocyclylalkyl. The alkyl, carbocyclylalkyl, or heterocyclylalkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R5 is xe2x80x94H, C1-C8-alkyl, xe2x80x94Oxe2x80x94R6, xe2x80x94N(R6)(R7), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R5 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R6, xe2x80x94N(R6)(R7), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
R6 and R7 are independently selected from the group consisting of xe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R6 and R7 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, R6 and R7 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.
In some preferred embodiments, E5 is optionally-substituted heterocyclyl.
In some preferred embodiments, E5 is substituted carbocyclyl (preferably substituted phenyl). Such compounds include, for example: 
In some embodiments of this invention, the compound has a structure corresponding to Formula XVIII: 
A1, A2 and A3 are as defined above for Formula I.
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
In some preferred embodiments, E2 is C1-C20-alkyl, cycloalkyl, C1-C10-alkyl-cycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkyl-cycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more halogen.
In some preferred embodiments, E2 is C1-C6-alkyl. The alkyl optionally is substituted with one or more halogen.
E5 is substituted heterocyclyl.
In some preferred embodiments, E5 is heterocyclyl that is:
substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, and carbocyclyl-C1-C6-alkyl, and/or
substituted on the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming C5-C6-cycloalkyl or halo-C5-C6-cycloalkyl.
In some preferred embodiments, E5 is heterocyclyl that is:
substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6, and halogen-substituted carbocyclyl-C1-C6-alkyl, and/or
substituted on the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming C5-C6-cycloalkyl or halo-C5-C6-cycloalkyl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, and halo-C1-C8-alkyl.
R3 and R4 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, C1-C8-alkoxycarbonyl, C1-C8-alkylcarbonyl, carbocyclyl-C1-C8-alkyl, and carbocyclyl-C1-C8-alkoxycarbonyl.
R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C8-allyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
In some preferred embodiments, R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
R7 is xe2x80x94H, C1C8-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The alkyl, carbocyclylalkyl, or heterocyclylalkyl may be substituted with one or more halogen.
In some preferred embodiments, R7 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The alkyl, carbocyclylalkyl, and heterocyclylalkyl optionally are substituted with one or more halogen.
R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
In some preferred embodiments, R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
Compounds of this embodiment include, for example: 
In some embodiments of this invention, the compound has a structure corresponding to Formula XIX: 
A1, A2, and A3 are as defined above for Formula I.
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R1)(R2)xe2x80x94.
E2 comprises at least two carbon atoms. E2is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
In some preferred embodiments, E2 is C2-C20-alkyl, cycloalkyl, C1-C10-cycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkyl-cycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more halogen.
In some preferred embodiments, E2 is C2-C6-alkyl. The alkyl may optionally be substituted with one or more halogen.
E5 is optionally-substituted heterocyclyl.
In some preferred embodiments, E5 is heterocyclyl that is:
optionally substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, and carbocyclyl-C1-C6-alkyl, and/or
optionally substituted on the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming C5-C6-cycloalkyl or halo-C5-C6-cycloalkyl.
In some preferred embodiments, E5 is heterocyclyl that is:
optionally substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, keto, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R5)(R6), xe2x80x94C(O)(R7), xe2x80x94Sxe2x80x94R5, xe2x80x94S(O)2xe2x80x94R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl, and
optionally substituted on the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming C5-C6-cycloalkyl or halo-C5-C6-cycloalkyl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, and halo-C1-C8-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, and halo-C1-C6-alkyl.
R3 and R4 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, C1-C8-alkoxycarbonyl, C1-C8-alkylcarbonyl, carbocyclyl-C1C8-alkyl, and carbocyclyl-C1-C8-alkoxycarbonyl.
R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
In some preferred embodiments, R5 and R6 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
R7 is xe2x80x94H, C1-C8-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The alkyl, carbocyclylalkyl, and heterocyclylalkyl optionally are substituted with one or more halogen.
In some preferred embodiments, R7 is xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R8, xe2x80x94N(R8)(R9), carbocyclyl-C1-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The alkyl, carbocyclylalkyl, and heterocyclylalkyl optionally are substituted with one or more halogen.
R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
In some preferred embodiments, R8 and R9 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
Some particularly preferred compounds include: 
In some embodiments of this invention, the compound has a structure corresponding to Formula XX: 
A1, A2, and A3 are as defined above for Formula I.
E1 is xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94, or xe2x80x94(R1)(R2)xe2x80x94.
E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.
In some preferred embodiments, E2 is C2-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, and halo-C1-C6-alkyl.
In some preferred embodiments, E2 is C2-C6-alkyl. The alkyl may optionally be substituted with one or more halogen.
E3 is xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94(CO)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(NR3)xe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x80x94N(R4)xe2x80x94C(NR3)xe2x80x94, xe2x80x94C(NR3)xe2x80x94N(R4)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R4)xe2x80x94, xe2x80x94N(R4)xe2x80x94C(O)xe2x80x94, xe2x80x94N(R4)xe2x80x94C(O)xe2x80x94N(R5)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94N(R4)xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94N(R4)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R4)xe2x80x94N(R5)xe2x80x94C(O)xe2x80x94, xe2x80x94C(R4)(R6)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(R7)(R8)xe2x80x94.
E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.
In some preferred embodiments, E4 is a bond, C1-C20-alkyl, or C2-C20-alkenyl. The alkyl and alkenyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, and carbocyclyl. The carbocyclyl, in turn, optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, halo-C1-C8-alkyl, halo-C1-C8-alkoxy, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, halocarbocyclyl, and halogen-substituted carbocyclyl-C1-C8-alkyl.
In some preferred embodiments, E4 is a bond, C1-C3-alkyl, or C2-C3-alkenyl. The alkyl and alkenyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen and carbocyclyl. The carbocyclyl, in turn, optionally is substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, halocarbocyclyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.
E5 is carbocyclyl or heterocyclyl. The carbocyclyl and heterocyclyl are:
substituted with a substituent selected from the group consisting of optionally-substituted carbocyclyl, optionally-substituted carbocyclylalkyl, optionally-substituted heterocyclyl, and optionally-substituted heterocyclylalkyl, and
optionally substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, alkyl, alkoxy, alkoxyalkyl, xe2x80x94N(R11)(R12), xe2x80x94C(O)(R13), xe2x80x94Sxe2x80x94R11, xe2x80x94S(O)2xe2x80x94R11, carbocyclyl, carbocyclylalkyl, haloalkyl, haloalkoxy, halogen-substituted alkoxyalkyl, halocarbocyclyl, halogen-substituted carbocyclylalkyl, hydroxycarbocyclyl, and heteroaryl.
In some preferred embodiments, E5 is carbocyclyl or heterocyclyl. The carbocyclyl and heterocyclyl are:
substituted with a substituent selected from the group consisting of optionally-substituted carbocyclyl, optionally-substituted carbocyclyl-C1-C8-alkyl, optionally-substituted heterocyclyl, and optionally-substituted heterocyclyl-C1-C8-alkyl, and
optionally substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C8-alkyl, C1-C8-alkoxy, Cl-C8-alkoxy-C1-C8-alkyl, xe2x80x94N(R11)(R12), xe2x80x94C(O)(R13), xe2x80x94Sxe2x80x94R11, xe2x80x94S(O)2xe2x80x94R11, carbocyclyl, carbocyclyl-C1-C8-alkyl, halo-C1-C8-alkyl, halo-C1-C8-alkoxy, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, halocarbocyclyl, halogen-substituted carbocyclyl-C1-C8-alkyl, hydroxycarbocyclyl, and heteroaryl.
In some preferred embodiments, E5 is carbocyclyl or heterocyclyl, wherein the carbocyclyl and heterocyclyl are:
substituted with a substituent selected from the group consisting of optionally-substituted carbocyclyl, optionally-substituted carbocyclyl-C1-C6-alkyl, optionally-substituted heterocyclyl, and optionally-substituted heterocyclyl-C1-C6-alkyl, and
optionally substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, xe2x80x94N(R11)(R12), xe2x80x94C(O)(R13), xe2x80x94Sxe2x80x94R11, xe2x80x94S(O)2xe2x80x94R11, carbocyclyl, carbocyclyl-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, halocarbocyclyl, halogen-substituted carbocyclyl-C1-C6-alkyl, hydroxycarbocyclyl, and heteroaryl.
R1 and R2 are independently selected from the group consisting of xe2x80x94H and alkyl. The alkyl optionally is substituted.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, and halo-C1-C8-alkyl.
In some preferred embodiments, R1 and R2 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, and halo-C1-C6-alkyl.
R3 is xe2x80x94H or xe2x80x94OH .
R4 and R5 are independently selected from the group consisting of xe2x80x94H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted.
In some preferred embodiments, R4 and R5 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
In some preferred embodiments, R4 and R5 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
R6 is xe2x80x94CN or xe2x80x94OH .
R7 is xe2x80x94H, halogen, xe2x80x94OH, alkyl, alkoxy, or alkoxyalkyl. The alkyl, alkoxy, and alkoxyalkyl optionally are substituted.
In some preferred embodiments, R7 is xe2x80x94H, halogen, xe2x80x94OH, C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halo-C1C8-alkyl, halo-C1-C8-alkoxy, or halogen-substituted C1-C8-alkoxy-C1-C8-alkyl.
In some preferred embodiments, R7 is xe2x80x94H, halogen, xe2x80x94OH, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, or halogen-substituted C1-C6-alkoxy-C1-C6-alkyl.
R8 is xe2x80x94OH or alkoxy. The alkoxy optionally is substituted.
In some preferred embodiments, R8 is xe2x80x94OH, C1-C8-alkoxy, or halo-C1-C8-alkoxy.
In some preferred embodiments, R8 is xe2x80x94OH, C1-C6-alkoxy, or halo-C1-C6-alkoxy.
R9 and R10 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, C1-C8-alkoxycarbonyl, C1-C8-alkylcarbonyl, carbocyclyl-C1-C8-alkyl, and carbocyclyl-C1-C8-alkoxycarbonyl.
R11 and R12 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
In some preferred embodiments, R11 and R12 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
In some preferred embodiments, R11 and R12 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
R13 is xe2x80x94H, C1-C8-alkyl, xe2x80x94Oxe2x80x94R14, xe2x80x94N(R14)(R15), carbocyclyl-C1-C8-alkyl, heterocyclyl-C1-C8-alkyl, halo-C1-C8-alkyl, halogen-substituted carbocyclyl-C1-C8-alkyl, or halogen-substituted heterocyclyl-C1-C8-alkyl.
In some preferred embodiments, R13 is of xe2x80x94H, C1-C6-alkyl, xe2x80x94Oxe2x80x94R14, xe2x80x94N(R14)(R15), carbocyclyl-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, halo-C1-C6-alkyl, halogen-substituted carbocyclyl-C1-C6-alkyl, or halogen-substituted heterocyclyl-C1-C6-alkyl.
R14 and R15 are independently selected from the group consisting of xe2x80x94H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
In some preferred embodiments, R14 and R15 are independently selected from the group consisting of xe2x80x94H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is xe2x80x94H, any member of this group optionally is substituted with one or more halogen.
Some preferred compounds include, for example: 
The hydroxamate compound or salt preferably has an inhibitory activity against MMP-1 or MMP-14 that is substantially less than its inhibitory activity against MMP-2, MMP-9, or MMP-13. In other words, the hydroxamate compound or salt preferably has an in inhibition constant (Ki) against at least one of MMP-2, MMP-9, and MMP-13 that is no greater than about 0.1 times its inhibition constant(s) against at least one of MMP-1 and MMP-14. The inhibition constant of a compound or salt thereof may be determined using an in vitro inhibition assay, such as the Ki assay described below in Examples 55-89.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has a Ki against MMP-2 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki(s) against one or both of MMP-1 and MMP-14.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has a Ki against MMP-9 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki(s) against one or both of MMP-1 and MMP-14.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has a Ki against MMP-13 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki(s) against one or both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, a cardiovascular condition or arthritis.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has Ki""s against both MMP-2 and MMP-9 that are no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki(s) against one or both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, cancer, a cardiovascular condition, or an ophthalmologic condition.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has Ki""s against all of MMP-2, MMP-9, and MMP-13 that are no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki(s) against one or both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, cancer, a cardiovascular condition, arthritis, or an ophthalmologic condition.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has a Ki against MMP-2 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki""s against both MMP-1 and MMP-14.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has a Ki against MMP-9 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki""s against both MMP-1 and MMP-14.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has a Ki against MMP-13 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki""s against both MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, a cardiovascular condition or arthritis.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has Ki""s against both MMP-2 and MMP-9 that are no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki""s against both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, cancer, a cardiovascular condition, or an ophthalmologic condition.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has Ki""s against all of MMP-2, MMP-9, and MMP-3 that are no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki""s against both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, cancer, a cardiovascular condition, arthritis, or an ophthalmologic condition.
The activity and selectivity of a hydroxamate compound or salt may alternatively be determined using an in vitro IC50 assay, such as the IC50 assay described below in Examples 55-89. In that instance, the hydroxamate compound or salt preferably has an IC50 value against at least one of MMP-2, MMP-9, and MMP-13 that is no greater than about 0.1 times its IC50 value(s) against at least one of MMP-1 and MMP-14.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has an IC50 value against MMP-2 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its IC50 value(s) against one or both of MMP-1 and MMP-14.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has an IC50 value against MMP-9 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its IC50 value(s) against one or both of MMP-1 and MMP-14.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has an IC50 value against MMP-13 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its IC50 value(s) against one or both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, a cardiovascular condition or arthritis.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has IC50 values against both MMP-2 and MMP-9 that are no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its IC50 value(s) against one or both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, cancer, a cardiovascular condition, or an ophthalmologic condition.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has IC50 values against all of MMP-2, MMP-9, and MMP-13 that are no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its IC50 value(s) against one or both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, cancer, a cardiovascular condition, arthritis, or an ophthalmologic condition.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has an IC50 value against MMP-2 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its IC50 values against both MMP-1 and MMP-14.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has an IC50 value against MMP-9 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its IC50 values against both MMP-1 and MMP-14.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has an IC50 value against MMP-13 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its IC50 values against both MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, a cardiovascular condition or arthritis.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has IC50 values against both MMP-2 and MMP-9 that are no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its IC50 values against both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, cancer, a cardiovascular condition, or an ophthalmologic condition.
In some particularly preferred embodiments, the hydroxamate compound or salt preferably has IC50 values against all of MMP-2, MMP-9, and MMP-3 that are no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its IC50 values against both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, cancer, a cardiovascular condition, arthritis, or an ophthalmologic condition.
The compounds of this invention can be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be advantageous due to one or more of the salt""s physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil. In some instances, a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
Where a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt preferably is pharmaceutically acceptable. Pharmaceutically acceptable salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. In general, these salts typically may be prepared by conventional means with a compound of this invention by reacting, for example, the appropriate acid or base with the compound.
Pharmaceutically-acceptable acid addition salts of the compounds of this invention may be prepared from an inorganic or organic acid. Examples of suitable inorganic acids include hydrochloric, hydrobromic acid, hydroionic, nitric, carbonic, sulfuric, and phosphoric acid. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic, and sulfonic classes of organic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, b-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.
Pharmaceutically-acceptable base addition salts of the compounds of this invention include, for example, metallic salts and organic salts. Preferred metallic salts include alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts, and other physiological acceptable metal salts. Such salts may be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Preferred organic salts can be made from tertiary amines and quaternary amine salts, such as tromethamine, diethylamine, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl (C1-C6) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
Particularly preferred salts of the compounds of this invention include hydrochloric acid (HCl) salts and trifluoroacetate (CF3COOH or TFA) salts.
One embodiment of this invention is directed to a process for preventing or treating a pathological condition associated with MMP activity in a mammal (e.g., a human, companion animal, farm animal, laboratory animal, zoo animal, or wild animal) having or disposed to having such a condition. Such a condition may be, for example, tissue destruction, a fibrotic disease, pathological matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a kidney disease, a liver disease, an ophthalmologic disease, or a central nervous system disease. Specific examples of such conditions include osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion, tumor metastasis, tumor angiogenesis, a decubitis ulcer, a gastric ulcer, a corneal ulcer, periodontal disease, liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis, multiple sclerosis, dilated cardiomyopathy, epidermal ulceration, epidermolysis bullosa, aortic aneurysm, weak injury repair, an adhesion, scarring, congestive heart failure, post myocardial infarction, coronary thrombosis, emphysema, proteinuria, bone disease, chronic obstructive pulmonary diseases, and Alzheimer""s disease.
In some particularly preferred embodiments, the condition comprises arthritis.
In some particularly preferred embodiments, the condition comprises tumor invasion, tumor metastasis, or tumor angiogenesis.
In some particularly preferred embodiments, the condition comprises periodontal disease.
In some particularly preferred embodiments, the condition comprises atherosclerosis.
In some particularly preferred embodiments, the condition comprises multiple sclerosis.
In some particularly preferred embodiments, the condition comprises dilated cardiomyopathy.
In some particularly preferred embodiments, the condition comprises post myocardial infarction.
In some particularly preferred embodiments, the condition comprises congestive heart failure.
In some particularly preferred embodiments, the condition comprises chronic obstructive pulmonary disease.
The condition may alternatively (or additionally) be associated with TNF-xcex1 convertase activity. Examples of such a condition include inflammation (e.g., rheumatoid arthritis), autoimmune disease, graft rejection, multiple sclerosis, a fibrotic disease, cancer, an infectious disease (e.g., malaria, mycobacterial infection, meningitis, etc.), fever, psoriasis, a cardiovascular disease (e.g., post-ischemic reperfusion injury and congestive heart failure), a pulmonary disease, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage, acute phase responses like those seen with infections and sepsis and during shock (e.g., septic shock, hemodynamic shock, etc.), cachexia, and anorexia.
The condition may alternatively (or additionally) be associated with aggrecanase activity. Examples of such a condition include inflammation diseases (e.g., osteoarthritis, rheumatoid arthritis, joint injury, reactive arthritis, acute pyrophosphate arthritis, and psoriatic arthritis) and cancer.
In this patent, the phrase xe2x80x9cpreventing a conditionxe2x80x9d means reducing the risk of (or delaying) the onset of the condition in a mammal that does not have the condition, but is predisposed to having the condition. In contrast, the phrase xe2x80x9ctreating a conditionxe2x80x9d means ameliorating, suppressing, or eradicating an existing condition. The pathological condition may be (a) the result of pathological MMP activity itself, and/or (b) affected by MMP activity (e.g., diseases associated with TNF-xcex1).
A wide variety of methods may be used alone or in combination to administer the hydroxamates and salt thereof described above. For example, the hydroxamates or salts thereof may be administered orally, parenterally, by inhalation spray, rectally, or topically.
Typically, a compound (or pharmaceutically acceptable salt thereof) described in this patent is administered in an amount effective to inhibit a target MMP(s). The target MMP is/are typically MMP-2, MMP-9, and/or MMP-13, with MMP-13 often being a particularly preferred target. The preferred total daily dose of the hydroxamate or salt thereof (administered in single or divided doses) is typically from about 0.001 to about 100 mg/kg, more preferably from about 0.001 to about 30 mg/kg, and even more preferably from about 0.01 to about 10 mg/kg (i.e., mg hydroxamate or salt thereof per kg body weight). Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose. In many instances, the administration of the compound or salt will be repeated a plurality of times. Multiple doses per day typically may be used to increase the total daily dose, if desired.
Factors affecting the preferred dosage regimen include the type, age, weight, sex, diet, and condition of the patient; the severity of the pathological condition; the route of administration; pharmacological considerations, such as the activity, efficacy, pharmacokinetic, and toxicology profiles of the particular hydroxamate or salt thereof employed; whether a drug delivery system is utilized; and whether the hydroxamate or salt thereof is administered as part of a drug combination. Thus, the dosage regimen actually employed can vary widely, and, therefore, can deviate from the preferred dosage regimen set forth above.
This invention also is directed to pharmaceutical compositions comprising a hydroxamate or salt thereof described above, and to methods for making pharmaceutical compositions (or medicaments) comprising a hydroxamate or salt thereof described above.
The preferred composition depends on the method of administration, and typically comprises one or more conventional pharmaceutically acceptable carriers, adjuvants, and/or vehicles. Formulation of drugs is generally discussed in, for example, Hoover, John E., Remington""s Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.: 1975). See also, Liberman, H. A. See also, Lachman, L., eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, N.Y., 1980).
Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the hydroxamates or salts thereof are ordinarily combined with one or more adjuvants. If administered per os, the hydroxamates or salts thereof can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation, as can be provided in a dispersion of the hydroxamate or salt thereof in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms also can comprise buffering agents, such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills additionally can be prepared with enteric coatings.
Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also can comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
xe2x80x9cParenteral administrationxe2x80x9d includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) can be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents. Acceptable vehicles and solvents include, for example, water, 1,3-butanediol, Ringer""s solution, isotonic sodium chloride solution, bland fixed oils (e.g., synthetic mono- or diglycerides), fatty acids (e.g., oleic acid), dimethyl acetamide, surfactants (e.g., ionic and non-ionic detergents), and/or polyethylene glycols.
Formulations for parenteral administration may, for example, be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The hydroxamates or salts thereof can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, com oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
Suppositories for rectal administration can be prepared by, for example, mixing the drug with a suitable nonirritating excipient that is solid at ordinary temperatures, but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, such as cocoa butter; synthetic mono-, di-, or triglycerides; fatty acids; and/or polyethylene glycols
xe2x80x9cTopical administrationxe2x80x9d includes the use of transdermal administration, such as transdermal patches or iontophoresis devices.
Other adjuvants and modes of administration well-known in the pharmaceutical art may also be used.
The term xe2x80x9calkylxe2x80x9d (alone or in combination with another term(s)) means a straight- or branched-chain saturated hydrocarbyl typically containing from 1 to about 20 carbon atoms, more typically from 1 to about 8 carbon atoms, and even more typically from 1 to about 6 carbon atoms. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, and the like.
The term xe2x80x9calkenylxe2x80x9d (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl containing one or more double bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms, and even more typically from about 2 to about 6 carbon atoms. Examples of such substituents include ethenyl (vinyl); 2-propenyl; 3-propenyl; 1,4-pentadienyl; 4-butadienyl; 1-butenyl; 2-butenyl; 3-butenyl; decenyl; and the like.
The term xe2x80x9calkynylxe2x80x9d (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl containing one or more triple bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms, and even more typically from about 2 to about 6 carbon atoms. Examples of such substituents include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
The term xe2x80x9ccarbocyclylxe2x80x9d (alone or in combination with another term(s)) means a saturated cyclic (i.e., xe2x80x9ccycloalkylxe2x80x9d), partially saturated cyclic, or aryl hydrocarbyl containing from 3 to 14 carbon ring atoms (xe2x80x9cring atomsxe2x80x9d are the atoms bound together to form the ring or rings of a cyclic group). A carbocyclyl may be a single ring, which typically contains from 3 to 6 ring atoms. Examples of such single-ring carbocyclyls include cyclopropanyl, cyclobutanyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. A carbocyclyl alternatively may be 2 or 3 rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (also known as xe2x80x9ctetralinylxe2x80x9d), indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (also known as xe2x80x9cphenalenylxe2x80x9d), fluoreneyl, decalinyl, and norpinanyl.
The term xe2x80x9ccycloalkylxe2x80x9d (alone or in combination with another term(s)) means a saturated cyclic hydrocarbyl containing from 3 to 14 carbon ring atoms. A cycloalkyl may be a single carbon ring, which typically contains from 3 to 6 carbon ring atoms. Examples of single-ring cycloalkyls include cyclopropyl (or xe2x80x9ccyclopropanylxe2x80x9d), cyclobutyl (or xe2x80x9ccyclobutanylxe2x80x9d), cyclopentyl (or xe2x80x9ccyclopentanylxe2x80x9d), and cyclohexyl (or xe2x80x9ccyclohexanylxe2x80x9d). A cycloalkyl alternatively may be 2 or 3 carbon rings fused together, such as, decalinyl or norpinanyl.
The term xe2x80x9carylxe2x80x9d (alone or in combination with another term(s)) means an aromatic carbocyclyl containing from 6 to 14 carbon ring atoms. Examples of aryls include phenyl, naphthalenyl, and indenyl.
In some instances, the number of carbon atoms in a hydrocarbyl (e.g., alkyl, alkenyl, alkynyl, or cycloalkyl) is indicated by the prefix xe2x80x9cCx-Cy-xe2x80x9d, wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, xe2x80x9cC1-C6-alkylxe2x80x9d refers to an alkyl containing from 1 to 6 carbon atoms. Illustrating further, C3-C6-cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms.
The term xe2x80x9chydrogenxe2x80x9d (alone or in combination with another term(s)) means a hydrogen radical, and may be depicted as xe2x80x94H.
The term xe2x80x9chydroxyxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94OH.
The term xe2x80x9cnitroxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94NO2.
The term xe2x80x9ccyanoxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94CN, which also may be depicted as: 
The term xe2x80x9cketoxe2x80x9d (alone or in combination with another term(s)) means an oxo radical, and may be depicted as xe2x95x90O.
The term xe2x80x9ccarboxyxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)xe2x80x94OH, which also may be depicted as: 
The term xe2x80x9caminoxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94NH2. The term xe2x80x9cmonosubstituted aminoxe2x80x9d (alone or in combination with another term(s)) means an amino wherein one of the hydrogen radicals is replaced by a non-hydrogen substituent. The term xe2x80x9cdisubstituted aminoxe2x80x9d (alone or in combination with another term(s)) means an amino wherein both of the hydrogen atoms are replaced by non-hydrogen substituents, which may be identical or different.
The term xe2x80x9chalogenxe2x80x9d (alone or in combination with another term(s)) means a fluorine radical (which may be depicted as xe2x80x94F), chlorine radical (which may be depicted as xe2x80x94Cl), bromine radical (which may be depicted as xe2x80x94Br), or iodine radical (which may be depicted as xe2x80x94I). Typically, a fluorine radical or chlorine radical is preferred, with a fluorine radical often being particularly preferred.
If a substituent is described as being xe2x80x9csubstitutedxe2x80x9d, a non-hydrogen radical is in the place of a hydrogen radical on a carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen radical is in the place of a hydrogen radical on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro radical, and difluoroalkyl is alkyl substituted with two fluoro radicals. It should be recognized that if there are more than one substitutions on a substituent, each non-hydrogen radical may be identical or different (unless otherwise stated).
If a substituent is described as being xe2x80x9coptionally substitutedxe2x80x9d, the substituent may be either (1) substituted, or (2) not substituted.
This specification uses the terms xe2x80x9csubstituentxe2x80x9d and xe2x80x9cradicalxe2x80x9d interchangeably.
The prefix xe2x80x9chaloxe2x80x9d indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, haloalkyl means an alkyl wherein at least one hydrogen radical is replaced with a halogen radical. Examples of haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like. Illustrating further, xe2x80x9chaloalkoxyxe2x80x9d means an alkoxy wherein at least one hydrogen radical is replaced by a halogen radical. Examples of haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as xe2x80x9cperfluoromethyoxyxe2x80x9d), 1,1,1-trifluoroethoxy, and the like. It should be recognized that if a substituent is substituted by more than one halogen radical, those halogen radicals may be identical or different (unless stated otherwise).
The prefix xe2x80x9cperhaloxe2x80x9d indicates that every hydrogen radical on the substituent to which the prefix is attached is replaced with independently selected halogen radicals, i.e., each hydrogen radical on the substituent is replaced with a halogen radical. If all the halogen radicals are identical, the prefix typically will identify the halogen radical. Thus, for example, the term xe2x80x9cperfluoroxe2x80x9d means that every hydrogen radical on the substituent to which the prefix is attached is substituted with a fluorine radical. To illustrate, the term xe2x80x9cperfluoroalkylxe2x80x9d means an alkyl wherein a fluorine radical is in the place of each hydrogen radical. Examples of perfluoroalkyl substituents include trifluoromethyl (xe2x80x94CF3), perfluorobutyl, perfluoroisopropyl, perfluorododecyl, perfluorodecyl, and the like. To illustrate further, the term xe2x80x9cperfluoroalkoxyxe2x80x9d means an alkoxy wherein each hydrogen radical is replaced with a fluorine radical. Examples of perfluoroalkoxy substituents include trifluoromethoxy (xe2x80x94Oxe2x80x94CF3), perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy, perfluorodecoxy, and the like.
The term xe2x80x9ccarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)xe2x80x94, which also may be depicted as: 
This term also is intended to encompass a hydrated carbonyl substituent, i.e., xe2x80x94C(OH)2xe2x80x94.
The term xe2x80x9caminocarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)xe2x80x94NH2, which also may be depicted as: 
The term xe2x80x9coxyxe2x80x9d (alone or in combination with another term(s)) means an ether substituent, and may be depicted as xe2x80x94Oxe2x80x94.
The term xe2x80x9calkoxyxe2x80x9d (alone or in combination with another term(s)) means an alkylether, i.e., xe2x80x94O-alkyl. Examples of such a substituent include methoxy (xe2x80x94Oxe2x80x94CH3), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
The term xe2x80x9calkylcarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)-alkyl. For example, xe2x80x9cethylcarbonylxe2x80x9d may be depicted as: 
The term xe2x80x9caminoalkylcarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)-alkyl-NH2. For example, xe2x80x9caminomethylcarbonylxe2x80x9d may be depicted as: 
The term xe2x80x9calkoxycarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)xe2x80x94O-alkyl. For example, xe2x80x9cethoxycarbonylxe2x80x9d may be depicted as: 
The term xe2x80x9ccarbocyclylcarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)-carbocyclyl. For example, xe2x80x9cphenylcarbonylxe2x80x9d may be depicted as: 
Similarly, the term xe2x80x9cheterocyclylcarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)-heterocyclyl.
The term xe2x80x9ccarbocyclylalkylcarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)-alkyl-carbocyclyl. For example, xe2x80x9cphenylethylcarbonylxe2x80x9d may be depicted as: 
Similarly, the term xe2x80x9cheterocyclylalkylcarbonylxe2x80x9d (alone or in combination with another tern(s)) means xe2x80x94C(O)-alkyl-heterocyclyl.
The term xe2x80x9ccarbocyclyloxycarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)xe2x80x94O-carbocyclyl. For example, xe2x80x9cphenyloxycarbonylxe2x80x9d may be depicted as: 
The term xe2x80x9ccarbocyclylalkoxycarbonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(O)xe2x80x94O-alkyl-carbocyclyl. For example, xe2x80x9cphenylethoxycarbonylxe2x80x9d may be depicted as: 
The term xe2x80x9cthioxe2x80x9d or xe2x80x9cthiaxe2x80x9d (alone or in combination with another term(s)) means a thiaether, i.e., an ether substituent wherein a divalent sulfur atom is in the place of the ether oxygen atom. Such a substituent may be depicted as xe2x80x94Sxe2x80x94. This, for example, xe2x80x9calkyl-thioalkylxe2x80x9d means alkyl-S-alkyl.
The term xe2x80x9cthiolxe2x80x9d or xe2x80x9csulfhydrylxe2x80x9d (alone or in combination with another term(s)) means a sulfhydryl, and may be depicted as xe2x80x94SH.
The term xe2x80x9c(thiocarbonyl)xe2x80x9d (alone or in combination with another term(s)) means a carbonyl wherein the oxygen atom has been replaced with a sulfur. Such a substituent may be depicted as xe2x80x94C(S)xe2x80x94, and also may be depicted as: 
The term xe2x80x9calkyl(thiocarbonyl)xe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(S)-alkyl. For example, xe2x80x9cethyl(thiocarbonyl)xe2x80x9d may be depicted as: 
The term xe2x80x9calkoxy(thiocarbonyl)xe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(S)xe2x80x94O-alkyl. For example, xe2x80x9cethoxy(thiocarbonyl)xe2x80x9d may be depicted as: 
The term xe2x80x9ccarbocyclyl(thiocarbonyl)xe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(S)-carbocyclyl. For example, xe2x80x9cphenyl(thiocarbonyl)xe2x80x9d may be depicted as: 
Similarly, the term xe2x80x9cheterocyclyl(thiocarbonyl)xe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(S)-heterocyclyl.
The term xe2x80x9ccarbocyclylalkyl(thiocarbonyl)xe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(S)-alkyl-carbocyclyl. For example, xe2x80x9cphenylethyl(thiocarbonyl)xe2x80x9d may be depicted as: 
Similarly, the term xe2x80x9cheterocyclylalkyl(thiocarbonyl)xe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(S)-alkyl-heterocyclyl.
The term xe2x80x9ccarbocyclyloxy(thiocarbonyly)xe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(S)xe2x80x94O-carbocyclyl. For example, xe2x80x9cphenyloxy(thiocarbonyl)xe2x80x9d may be depicted as: 
The term xe2x80x9ccarbocyclylalkoxy(thiocarbonyl)xe2x80x9d (alone or in combination with another term(s)) means xe2x80x94C(S)xe2x80x94O-alkyl-carbocyclyl. For example, xe2x80x9cphenylethoxy(thiocarbonyl)xe2x80x9d may be depicted as: 
The term xe2x80x9csulfonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94S(O)2xe2x80x94, which also may be depicted as: 
Thus, for example, xe2x80x9calkyl-sulfonyl-alkylxe2x80x9d means alkylxe2x80x94S(O)2-alkyl.
The term xe2x80x9caminosulfonylxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94S(O)2xe2x80x94NH2, which also may be depicted as: 
The term xe2x80x9csulfoxidoxe2x80x9d (alone or in combination with another term(s)) means xe2x80x94S(O)xe2x80x94, which also may be depicted as: 
Thus, for example, xe2x80x9calkyl-sulfoxido-alkylxe2x80x9d means alkylxe2x80x94S(O)-alkyl.
The term xe2x80x9cheterocyclylxe2x80x9d (alone or in combination with another term(s)) means a saturated (i.e., xe2x80x9cheterocycloalkylxe2x80x9d), partially saturated, or aryl (i.e., xe2x80x9cheteroarylxe2x80x9d) ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
A heterocyclyl may be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples of single-ring heterocyclyls include furanyl, dihydrofurnayl, tetrahydrofuranyl, thiophenyl (also known as xe2x80x9cthiofuranylxe2x80x9d), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as xe2x80x9cazoximylxe2x80x9d), 1,2,5-oxadiazolyl (also known as xe2x80x9cfurazanylxe2x80x9d), or 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, or 1,3,4dioxazolyl), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl (including 1,2-pyranyl or 1,4-pyranyl), dihydropyranyl, pyridinyl (also known as xe2x80x9cazinylxe2x80x9d), piperidinyl, diazinyl (including pyridazinyl (also known as xe2x80x9c1,2-diazinylxe2x80x9d), pyrimidinyl (also known as xe2x80x9c1,3-diazinylxe2x80x9d), or pyrazinyl (also known as xe2x80x9c1,4diazinylxe2x80x9d)), piperazinyl, triazinyl (including s-triazinyl (also known as xe2x80x9c1,3,5-triazinylxe2x80x9d), as-triazinyl (also known 1,2,4-triazinyl), and v-triazinyl (also known as xe2x80x9c1,2,3-triazinylxe2x80x9d)), oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as xe2x80x9cpentoxazolylxe2x80x9d), 1,2,6-oxazinyl, or 1,4-oxazinyl), isoxazinyl (including o-isoxazinyl or p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl or 1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.
A heterocyclyl alternatively may be 2 or 3 rings fused together, such as, for example, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl. Other examples of fused-ring heterocyclyls include benzo-fused heterocyclyls, such as indolyl, isoindolyl (also known as xe2x80x9cisobenzazolylxe2x80x9d or xe2x80x9cpseudoisoindolylxe2x80x9d), indoleninyl (also known as xe2x80x9cpseudoindolylxe2x80x9d), isoindazolyl (also known as xe2x80x9cbenzpyrazolylxe2x80x9d), benzazinyl (including quinolinyl (also known as xe2x80x9c1-benzazinylxe2x80x9d) or isoquinolinyl (also known as xe2x80x9c2-benzazinylxe2x80x9d)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (also known as xe2x80x9c1,2-benzodiazinylxe2x80x9d) or quinazolinyl (also known as xe2x80x9c1,3-benzodiazinylxe2x80x9d)), benzopyranyl (including xe2x80x9cchromanylxe2x80x9d or xe2x80x9cisochromanylxe2x80x9d), benzothiopyranyl (also known as xe2x80x9cthiochromanylxe2x80x9d), benzoxazolyl, indoxazinyl (also known as xe2x80x9cbenzisoxazolylxe2x80x9d), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also known as xe2x80x9ccoumaronylxe2x80x9d), isobenzofuranyl, benzothienyl (also known as xe2x80x9cbenzothiophenylxe2x80x9d, xe2x80x9cthionaphthenylxe2x80x9d, or xe2x80x9cbenzothiofuranylxe2x80x9d), isobenzothienyl (also known as xe2x80x9cisobenzothiophenylxe2x80x9d, xe2x80x9cisothionaphthenylxe2x80x9d, or xe2x80x9cisobenzothiofuranylxe2x80x9d), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, or 3,1,4-benzoxazinyl), benzisoxazinyl (including 1,2-benzisoxazinyl or 1,4-benzisoxazinyl), tetrahydroisoquinolinyl, carbazolyl, xanthenyl, and acridinyl.
The term xe2x80x9c2-fused""ringxe2x80x9d heterocyclyl (alone or in combination with another term(s)) means a saturated, partially saturated, or aryl heterocyclyl containing 2 fused rings. Examples of 2-fused-ring heterocyclyls include indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzolinanyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl.
The term xe2x80x9cheteroarylxe2x80x9d (alone or in combination with another term(s)) means an aromatic heterocyclyl containing from 5 to 14 ring atoms. A heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as 1,3,5-, 1,2,4- or 1,2,3-tiiazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as 1,2-, 1,4-, 2,3- and 2,1-benzopyronyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl.
A carbocyclyl or heterocyclyl can optionally be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, keto, alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl (also known as xe2x80x9calkanoylxe2x80x9d), aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, and cycloalkylalkoxycarbonyl. More typically, a carbocyclyl or heterocyclyl may optionally be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94C(O)xe2x80x94OH, keto, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkylcarbonyl, aryl, aryl-C1-C6-alkyl, aryl-C1-C6-alkoxy, aryl-C1-C6-alkoxy-C1-C6-alkyl, aryl-C1-C6-alkoxycarbonyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, cycloalkyl-C1-C6-alkoxy, cycloalkyl-C1-C6-alkoxy-C1-C6-alkyl, and cycloalkyl-C1-C6-alkoxycarbonyl. The alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl, aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, or arylalkoxycarbonyl substituent(s) may further be substituted with, for example, one or more halogen. The aryls or cycloalkyls are typically single-ring substituents containing from 3 to 6 ring atoms, and more typically from 5 to 6 ring atoms.
An aryl or heteroaryl can optionally be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94SH, xe2x80x94C(O)xe2x80x94OH, amino, aminocarbonyl, aminoalkyl, alkyl, alkylthio, carboxyalkylthio, alkylcarbonyl, alkylcarbonyloxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxyalkylthio, alkoxycarbonylalkylthio, carboxyalkoxy, alkoxycarbonylalkoxy, carbocyclyl, carbocyclylalkyl, carbocyclyloxy, carbocyclylthio, carbocyclylalkylthio, carbocyclylamino, carbocyclylalkylamino, carbocyclylcarbonylamino, carbocyclylcarbonyl, carbocyclylalkyl, carbonyl, carbocyclylcarbonyloxy, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, carbocyclyloxyalkoxycarbocyclyl, carbocyclylthioalkylthiocarbocyclyl, carbocyclylthioalkoxycarbocyclyl, carbocyclyloxyalkylthiocarbocyclyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylthio, heterocyclylamino, heterocyclylalkylamino, heterocyclylcarbonylamino, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, heterocyclyloxycarbonyl, heterocyclylcarbonyloxy, heterocyclylalkoxycarbonyl, heterocyclyloxyalkoxyheterocyclyl, heterocyclylthioalkylthioheterocyclyl, heterocyclylthioalkoxyheterocyclyl, and heterocyclyloxyalkylthioheterocyclyl. More typically, an aryl or heteroaryl may, for example, optionally be substituted with one or more substituents independently selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94SH, xe2x80x94C(O)xe2x80x94OH, amino, aminocarbonyl, amino-C1-C6-alkyl, C1-C6-alkyl, C1-C6-alkylthio, carboxy-C1-C6-alkylthio, C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyloxy, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkylthio, C1-C6-alkoxycarbonyl-C1-C6-alkylthio, carboxy-C1-C6-alkoxy, C1-C6-alkoxycarbonyl-C1-C6-alkoxy, aryl, aryl-C1-C6-alkyl, aryloxy, arylthio, aryl-C1-C6-alkylthio, arylamino, aryl-C1-C6-alkylamino, arylcarbonylamino, arylcarbonyl, aryl-C1-C6-alkylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, aryl-C1-C6-alkoxycarbonyl, aryloxy-C1-C6-alkoxyaryl, arylthio-C1-C6-alkylthioaryl, arylthio-C1-C6-alkoxyaryl, aryloxy-C1-C6-alkylthioaryl, cycloalkyl, cycloalkyl-C1-C6-alkyl, cycloalkyloxy, cycloalkylthio, cycloalkyl-C1-C6-alkylthio, cycloalkylamino, cycloalkyl-C1-C6-alkylamino, cycloalkylcarbonylamino, cycloalkylcarbonyl, cycloalkyl-C1-C6-alkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyloxycarbonyl, cycloalkyl-C1-C6-alkoxycarbonyl, heteroaryl, heteroaryl-C1-C6-alkyl, heteroaryloxy, heteroarylthio, heteroaryl-C1-C6-alkylthio, heteroarylamino, heteroaryl-C1-C6-alkylamino, heteroarylcarbonylamino, heteroarylcarbonyl, heteroaryl-C1-C6-alkylcarbonyl, heteroaryloxycarbonyl, heteroarylcarbonyloxy, and heteroaryl-C1-C6-alkoxycarbonyl. Here, one or more hydrogen bound to a carbon in any such substituent may, for example, optionally be replaced with halogen. In addition, the cycloalkyl, aryl, and heteroaryl are typically single-ring substituents containing 3 to 6 ring atoms, and more typically 5 or 6 ring atoms.
A prefix attached to a multi-component substituent only applies to the first component. To illustrate, the term xe2x80x9calkylcycloalkylxe2x80x9d contains two components: alkyl and cycloalkyl. Thus, the C1-C6-prefix on C1-C6-alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the C1-C6-prefix does not describe the cycloalkyl component. To illustrate further, the prefix xe2x80x9chaloxe2x80x9d on haloalkoxyalkyl indicates that only the alkoxy component of the alkoxyalkyl substituent is substituted with one or more halogen radicals. If halogen substitution may alternatively or additionally occur on the alkyl component, the substituent would instead be described as xe2x80x9chalogen-substituted alkoxyalkylxe2x80x9d rather than xe2x80x9chaloalkoxyalkyl.xe2x80x9d And finally, if the halogen substitution may only occur on the alkyl component, the substituent would instead be described as xe2x80x9calkoxyhaloalkyl.xe2x80x9d
If substituents are described as being xe2x80x9cindependently selectedxe2x80x9d from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).
When words are used to describe a substituent, the rightmost-described component of the substituent is the component that has the free valence. To illustrate, benzene substituted with methoxyethyl has the following structure: 
As can be seen, the ethyl is bound to the benzene, and the methoxy is the component of the substituent that is the component furthest from the benzene. As further illustration, benzene substituted with cyclohexanylthiobutoxy has the following structure: 
When words are used to describe a linking element between two other elements of a depicted chemical structure, the rightmost-described component of the substituent is the component that is bound to the left element in the depicted structure. To illustrate, if the chemical structure is Xxe2x80x94Lxe2x80x94Y and L is described as methylcyclohexanylethyl, then the chemical would be X-ethyl-cyclohexanyl-methyl-Y.
When a chemical formula is used to describe a substituent, the dash on the left side of the formula indicates the portion of the substituent that has the free valence. To illustrate, benzene substituted with xe2x80x94C(O)xe2x80x94OH has the following structure: 
When a chemical formula is used to describe a linking element between two other elements of a depicted chemical structure, the leftmost dash of the substituent indicates the portion of the substituent that is bound to the left element in the depicted structure. The rightmost dash, on the other hand, indicates the portion of the substituent that is bound to the right element in the depicted structure. To illustrate, if the depicted chemical structure is Xxe2x80x94Lxe2x80x94Y and L is described as xe2x80x94C(O)xe2x80x94N(H)xe2x80x94, then the chemical would be: 
The term xe2x80x9cpharmaceutically acceptablexe2x80x9d is used adjectivally in this patent to mean that the modified noun is appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product.
With reference to the use of the words xe2x80x9ccomprisexe2x80x9d or xe2x80x9ccomprisesxe2x80x9d or xe2x80x9ccomprisingxe2x80x9d in this patent (including the claims), Applicants note that unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that Applicants intend each of those words to be so interpreted in construing this patent, including the claims below.
The detailed examples below illustrate preparation of compounds and salts of this invention. Other compounds and salts of this invention may be prepared using the methods illustrated in these examples (either alone or in combination with techniques generally known in the art). Such known techniques include, for example, those disclosed in Int""l Publ. No. WO 99/25687 (PCT Patent Application No. PCT/US98/23242 published on May 27, 1999) (incorporated herein by reference). Such known techniques also include, for example, those disclosed in Int""l Publ. No. WO 00/50396 (PCT Patent Application No. PCT/US00/02518 published on Aug. 31, 2000) (incorporated herein by reference). Such known techniques further include, for example, those disclosed in Int""l Publ. No. WO 00/69821 (PCT Patent Application No. PCT/US00/06719 published on Nov. 23, 2000) (incorporated herein by reference).